Substituted pyrrolo-pyrazole derivatives active as kinase inhibitors

ABSTRACT

Substituted pyrrolo-pyrazole derivatives of formula (I) and pharmaceutically acceptable salts thereof, as defined in the specification, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful in therapy in the treatment of diseases associated with dysregulated protein kinase activity, like cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of co-pending application having U.S. Ser. No. 12/096,989, filed on Jun. 11, 2008, which is a '371 of international application having Serial No. PCT/EP2006/069373, the contents of all of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to certain substituted bicyclic pyrazole compounds, which modulate the activity of protein kinases. The compounds of this invention are therefore useful in treating diseases caused by dysregulated protein kinase activity. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.

2. Discussion of the Background

The insulin-like growth factor 1 receptor (IGF-1R, IGF1R) is a member of the insulin receptor subfamily of receptor tyrosine kinases (RTKs). IGF-1R mature protein consists of two alpha chains, which are extracellular and contain ligand-binding function, and two beta chains, which span the cell membrane and contain the intracellular kinase domains. This disulphide-linked (alpha/beta)2 heterodimer complex is able to bind and be activated by the ligands insulin-like growth factor-1 and -2 (IGF-1 and IGF-2), two circulating growth factors which are believed to mediate many of the effects of Growth Hormone (GH), and which have important physiological roles in foetal and post-natal growth and metabolism. Extracellular ligand binding to IGF-1R results in intracellular tyrosine kinase activation, and like several other RTKs such as the EGF and PDGF receptors, the activated receptor has potent mitogenic, motogenic and anti-apoptotic activity in a wide range of cell types: notably, it directly activates at least two major cell signalling pathways, the ras/MAPK pathway, through recruitment of SHC, and the PI-3 kinase/AKT(PKB) pathway, through recruitment and phosphorylation of the IRS adapter proteins. There is much evidence, both at preclinical and clinical levels, linking increased IGF-1R signalling to development and progression of cancer. This evidence includes observation that IGF-1R is able to induce cellular transformation, that fibroblasts from animals lacking IGF-1R through genetic ablation are extremely resistant to the transforming activity of a wide range of oncogenes, and that IGFs are potent anti-apoptotic agents. Studies of interference with receptor activity through various approaches have demonstrated that inhibition of IGF-1R dependent signalling can result in single agent antitumor activity, and in the enhancement of the activity of a wide range of chemotherapeutic agents and radiotherapy in human tumor cells cultured in vitro, as well as in animal models of disease, including human tumor xenograft models. Such IGF-1R inhibition strategies have included cellular transfection with dominant negative IGF-1R constructs or antisense oligonucleotides, use of IGF binding antagonists and blocking monoclonal antibodies directed against the extracellular receptor, and, significantly, selective small molecule inhibitors of IGF-1R kinase activity. Additional indication that IGF-1R signalling contributes to development of cancer, and thus that inhibition of this receptor may represent a valuable therapeutic option, is provided by the observation that high circulating levels of IGF-1 in human are associated with increased lifetime risk of developing several tumor types, including breast, colorectal, prostate and ovarian cancers, and with poor outcome in multiple myeloma. Importantly, gene and protein expression studies performed on clinical samples have revealed that IGF-1R and its ligands are frequently expressed in a wide range of human tumors. For an overview of IGFs and IGF-1R signalling, physiological function, and detailed description of the evidence supporting involvement of this system in human cancer that is summarised above, as well as in other pathologies, the reader is directed to the many reviews on the subject and references contained therein, for example Baserga R., Bongo A., Rubini M., Prisco M. and Valentinis B. Biochim Biophys Acta vol. 1332 pages F105-F126, 1997; Khandwala H. M., McCutcheon I. E., Flyvbjerg A. and Friend K. E. Endocr Rev vol. 21, pages 215-44, 2000; Le Roith D., Bondy C., Yakar S., Liu J. L. and Butler A. Endocr Rev. vol. 22, pages 53-74, 2001; Valentinis B., and Baserga R. Mol. Pathol. vol. 54, pages 133-7, 2001; Wang Y. and Sun Y., Curr Cancer Drug Targets vol. 2 pages 191-207, 2002, Laron, Z. J Clin Endocrinol Metab vol. 89, pages 1031-1044, 2004; Hofmann F and Garcia-Echeverria C. Drug Discov Today vol. 10, pages 1041-7, 2005.

SUMMARY OF THE INVENTION

It has been found that compounds of formula (I), described below, are inhibitors of the tyrosine kinase activity of the IGF-1 receptor.

Accordingly, a first object of the present invention is to provide a substituted bicyclic pyrrolo[3,4-c]pyrazole compound represented by formula (I),

wherein: R is an optionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl or aryl; R1 is selected from halogen, nitro, NHCOR4, NHSO₂R10, NR5R6, OR7, R8R9N—C₁-C₆ alkyl, R7O—C₁-C₆ alkyl and an optionally further substituted straight or branched C₁-C₆ alkyl, wherein:

-   -   R4 is selected from hydrogen, an optionally further substituted         straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,         heterocycloalkyl, aryl, NR8R9, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆         alkyl;     -   R5 and R6, being the same or different, are independently         selected from hydrogen, an optionally further substituted         straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,         heterocycloalkyl, aryl, R8R9N—C₂-C₆ alkyl and R7O—C₂-C₆ alkyl;     -   R7 is selected from hydrogen, an optionally further substituted         straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,         heterocycloalkyl, aryl and R8R9N—C₂-C₆ alkyl;     -   R8 and R9, being the same or different, are independently         selected from hydrogen, an optionally further substituted         straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,         heterocycloalkyl and aryl, or R8 and R9, taken together with the         nitrogen atom to which they are bonded, form an optionally         substituted heterocycloalkyl group;     -   R10 is an optionally further substituted straight or branched         C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl or aryl;         A, B, D and E represent a nitrogen atom, CH, CR2 or CR3, with a         maximum of two of A, B, D and E representing a nitrogen atom,         and with a maximum of two of A, B, D and E representing CR2 or         CR3, wherein:     -   R2 and R3, being the same or different, are independently         selected from halogen, trifluoromethyl, nitro, OR7, NR8R9, an         optionally further substituted straight or branched C₁-C₆ alkyl,         R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl, wherein R7, R8, and R9         are as defined above;         Ra and Rb, being the same or different, are selected from         hydrogen or methyl, with the provisos that:         when Ra and Rb are hydrogen atoms, and each of A, B, D and E are         CH, CR2 or CR3, then R1 is not OH, OCH₃, Cl, F or CH₃; and         when A, D and E are CH, and B is CR2, wherein R2 is         4-methylpiperazine or morpholine, then R1 is not         trifluoromethyl, F, nitro, amino, NHCOR4^(I) wherein R4^(I) is         isopropyl [—CH(CH₃)₂], cyclobutyl, —CH₂NHCH₃, —CH₂N(CH₃)₂,         —CH(NH₂)CH₃ or pyrrolidin-2-yl;         or isomers, tautomers, carriers, metabolite, prodrugs and         pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating diseases caused by and/or associated with dysregulated protein kinase activity, particularly IGF-1R or Aurora kinases activity, and more particularly IGF-1R kinase activity, which comprises administering to a mammal in need thereof an effective amount of a substituted pyrrolo pyrazole compound represented by formula (I) as above defined.

A preferred method of the present invention is to treat a disease caused by and/or associated with dysregulated protein kinase activity selected from the group consisting of cancer, cell proliferative disorders, viral infections, retinopathies including diabetic and neonatal retinopathies and age related macular degeneration, atherosclerosis and conditions involving vascular smooth muscle proliferation or neointimal formation such as restenosis following angioplasty or surgery, graft vessel disease, such as can occur following vessel or organ transplantation, acromegaly and disorders secondary to acromegaly as well as other hypertrophic conditions in which IGF/IGF-1R signalling is implicated, such as benign prostatic hyperplasia, psoriasis, fibrotic lung disease, pulmonary fibrosis, pathologies related to chronic or acute oxidative stress or hyperoxia induced tissue damage, and metabolic disorders in which elevated IGF levels or IGF-1R activity are implicated, such as obesity.

Another preferred method of the present invention is to treat specific types of cancer including carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratocanthomas, thyroid follicular cancer and Kaposi's sarcoma. Another preferred method of the present invention is to treat specific types of cancer such as, but not restricted to, breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer, gastric cancer, clear cell renal cell carcinoma, uveal melanoma, multiple myeloma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi' sarcoma, and medulloblastoma.

Another preferred method of the present invention is to treat cell proliferative disorders such as, but not restricted to, benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis.

In addition, the method of the present invention also provides tumor angiogenesis and metastasis inhibition.

The present invention also provides methods of synthetizing the substituted pyrrolo pyrazole derivatives of formula (I) prepared through a process consisting of standard synthetic transformations.

The present invention also provides a pharmaceutical composition comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, carrier or diluent.

The present invention further provides a pharmaceutical composition comprising a compound of formula (I) in combination with one or more chemotherapeutic agents or radiotherapy. Such agents can include, but are not limited to, antihormonal agents such as antiestrogens, antiandrogens and aromatase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, agents that target microtubules, platin-based agents, alkylating agents, DNA damaging or intercalating agents, antineoplastic antimetabolites, other kinase inhibitors, other anti-angiogenic agents, inhibitors of kinesins, therapeutic monoclonal antibodies, inhibitors of mTOR, histone deacetylase inhibitors, farnesyl transferase inhibitors, and inhibitors of hypoxic response.

DETAILED DESCRIPTION OF THE INVENTION

Several fused bicyclic compounds comprising pyrazole moieties and possessing kinase inhibitory activity have been disclosed in WO 00/69846, WO 02/12242, WO 03/028720, WO 03/097610, WO 04/007504, WO 04/013146, US2005/0026984 and WO 2005030776. The compounds of formula (I) may have one or more asymmetric centres, and may therefore exist as individual optical isomers or racemic mixtures. Accordingly, all the possible isomers, and their mixtures, of the compounds of formula (I) are within the scope of the present invention.

Derivatives of compounds of formula (I) originating from metabolism in a mammal, and the pharmaceutically acceptable bio-precursors (otherwise referred to as pro-drugs) of the compounds of formula (I) are also within the scope of the present invention.

In addition to the above, as known to those skilled in the art, the unsubstituted nitrogen on the pyrazole ring of the compounds of formula (I) rapidly equilibrates in solution to form a mixture of tautomers, as depicted below:

wherein R, R1, Ra and Rb, and A, B, D, E are as defined above.

Accordingly, in the present invention, where only one tautomer is indicated for the compounds of formula (I), the other tautomer (Ia) is also within the scope of the present invention, unless specifically noted otherwise.

In compounds of formula (I), the skilled person will recognize that the meaning of A, B, D, and E is such that the resulting six-membered ring linked to the aminopyrazole group through an amidic bond is an aromatic ring, optionally substituted by up to three substituents. Representative and not limiting examples of ring systems are the following:

The general terms as used herein, unless otherwise specified, have the meaning reported below.

The term “straight or branched C₁-C₆ alkyl” refers to a saturated aliphatic hydrocarbon radical, including straight chain and branched chain groups of from 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent groups are preferably one to three, independently selected from the group consisting of halogen, trifluoromethyl, alkylthio, cyano, nitro, formyl, alkylcarbonyl, alkylsulfonyl, carboxy, carboxamido, monoalkylcarboxamido, dialkylcarboxamido, hydroxyalkyl, OR7, NR8R9, aryl or arylalkyl, wherein R7, R8 and R9 are as defined above.

The term “C₃-C₆ cycloalkyl” refers to a 3- to 6-membered all-carbon monocyclic ring, which may contain one or more double bonds but does not have a completely conjugated π-electron system. Examples of cycloalkyl groups, without limitation, are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene and cyclohexadiene. A cycloalkyl group may be substituted or unsubstituted. When sustituted, the substituent groups are preferably one or two substituents, independently selected from the group consisting of halogen, trifluoromethyl, alkylthio, cyano, nitro, formyl, alkylcarbonyl, alkylsulfonyl, carboxy, carboxamido, monoalkylcarboxamido, dialkylcarboxamido, hydroxyalkyl, OR7, NR8R9, aryl and arylalkyl, wherein R7, R8 and R9 are as defined above.

The term “heterocycloalkyl” refers to a 3- to 7-membered, saturated or partially unsaturated carbocyclic ring where one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur. Not limiting examples of heterocycloalkyl groups are, for instance, oxirane, aziridine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, pyrrolidine, dihydropyrrole, pyran, dihydropyran, tetrahydropyran, tetrahydrothiopyran, piperidine, pyrazoline, isoxazolidine, isoxazoline, thiazolidine, thiazoline, isothiazoline, dioxane, piperazine, morpholine, thiomorpholine, examethyleneimine, homopiperazine and the like. An heterocycloalkyl group may be substituted or unsubstituted. When substituted, the substituent groups are preferably one or two substituents, independently selected from the group consisting of halogen, trifluoromethyl, alkylthio, cyano, nitro, formyl, alkylcarbonyl, alkylsulfonyl, carboxy, carboxamido, monoalkylcarboxamido, dialkylcarboxamido, hydroxyalkyl, OR7, NR8R9, aryl and arylalkyl, wherein R7, R8 and R9 are as defined above.

The term “aryl” refers to a mono-, bi- or poly-carbocyclic as well as heterocyclic hydrocarbon with from 1 to 4 ring systems, either fused or linked to each other by single bonds, wherein at least one of the carbocyclic or heterocyclic rings is aromatic. Not limiting examples of aryl groups are, for instance, phenyl, α- or β-naphthyl, 9,10-dihydroanthracenyl, indanyl, fluorenyl, biphenyl, pyrrolyl, furoyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl and the like.

The term “aryl” may also refer to aromatic carbocyclic or heterocyclic rings further fused or linked to non-aromatic heterocyclic rings, typically 5- to 7-membered heterocycles. Not limiting examples of such aryl groups are, for instance, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl; benzopyranyl, 2,3-dihydrobenzoxazinyl, 2,3-dihydroquinoxalinyl and the like.

The aryl group can be optionally substituted by one to three, preferably one or two, substituents selected from an optionally further substituted straight or branched C₁-C₆ alkyl, halogen, trifluoromethyl, alkylthio, cyano, nitro, formyl, alkylcarbonyl, alkylsulfonyl, carboxy, carboxamido, monoalkylcarboxamido, dialkylcarboxamido, hydroxyalkyl, OR7 and NR8R9, wherein R7, R8 and R9 are as defined above.

The term “halogen” indicates fluorine, chlorine, bromine or iodine.

The term “trifluoromethyl” indicates a —CF₃ group.

The term “hydroxyalkyl” indicates a hydroxy group linked to an alkyl group. Examples of hydroxyalkyl groups are hydroxymethyl (—CH₂OH), hydroxyethyl (—CH₂CH₂OH) and the like.

The term “alkylthio” indicates an alkyl group linked to a sulphur atom (—S-alkyl). Examples of alkylhio groups are methylthio (—SCH₃), ethylthio (—SCH₂CH₃), isopropylthio [—SCH(CH₃)₂] and the like.

The term “alkylcarbonyl” indicates an alkyl residue linked to a CO group [—C(═O)alkyl]. Examples of alkylcarbonyl are methylcarbonyl [—C(═O)CH₃], ethylcarbonyl [—C(═O)CH₂CH₃] and the like.

The term “alkylsulfonyl” indicates a —SO₂alkyl group. Examples of alkylsulfonyl groups are methylsulfonyl (—SO₂CH₃), ethylsulfonyl (—SO₂CH₂CH₃) and the like.

The term “arylalkyl” indicates an aryl group linked to a C₁-C₄ alkyl chain. Examples of aryalkyl are benzyl (—CH₂Ph), phenetyl (—CH₂CH₂Ph) and the like.

The terms “monoalkylcarboxamido” or “dialkylcarboxamido” indicate a carboxamido group where one or both hydrogens are substituted by an alkyl group. Examples of monoalkylcarboxamido are methylcarboxamido (—CONHCH₃), ethylcarboxamido (—CONHCH₂CH₃), and the like. Examples of dialkylcarboxamido are dimethylcarboxamido [—CON(CH₃)₂], diethylcarboxamido [—CON(CH₂CH₃)₂] and the like.

The term “pharmaceutically acceptable salt” of compounds of formula (I) refers to those salts that retain the biological effectiveness and properties of the parent compounds.

Such salts include:

acid addition salt with inorganic acids such as hydrochloric, hydrobromic, nitric, phosphoric, sulfuric, perchloric acid and the like, or with organic acids such as acetic, trifluoroacetic, propionic, glycolic, lactic, (D) or (L) malic, maleic, methanesulfonic, ethanesulfonic, benzoic, p-toluenesulfonic, salicylic, cinnamic, mandelic, tartaric, citric, succinic, malonic acid and the like; salts formed when an acidic proton present in a compound of formula (I) is either replaced by a metal ion, e.g., an alkali metal ion such as sodium or potassium, or an alkaline earth ion such as calcium or magnesium, or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

Preferred compounds of formula (I) are the compounds wherein:

R is selected from C₃-C₆ cycloalkyl, heterocycloalkyl and aryl; R1 is selected from halogen, NHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl, R7O—C₁-C₆ alkyl and an optionally further substituted straight or branched C₁-C₆ alkyl; A and D are CH or nitrogen, B is nitrogen, CH or CR2, and E is CH or CR3; R2 and R3 are independently selected from halogen, trifluoromethyl, OR7, NR8R9, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl.

Other preferred compounds of formula (I) are the compounds wherein:

R is selected from C₃-C₆ cycloalkyl, heterocycloalkyl and aryl; R1 is selected from NHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl, R7O—C₁-C₆ alkyl and an optionally further substituted straight or branched C₁-C₆ alkyl; A is CH or nitrogen, B is nitrogen, CH or CR2, E is CH or CR3, and D is CH; R2 and R3 are independently selected from halogen, OR7, NR8R9, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl.

Further preferred compounds of formula (I) are the compounds wherein:

R is heterocycloalkyl or aryl; R1 is selected from NHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl and an optionally further substituted straight or branched C₁-C₆ alkyl;

B is CH or CR2, E is CH or CR3, and A and D are CH;

R2 and R3 are independently selected from halogen, OR7, NR8R9, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl; Ra and Rb are methyl.

Particularly preferred compounds of formula (I) are the compounds wherein:

R is aryl; R1 is selected from NHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl and an optionally further substituted straight or branched C₁-C₆ alkyl;

B and E are CH, CR2 or CR3, and A and D are CH;

R2 and R3 are independently selected from halogen, OR7, NR8R9, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl; Ra and Rb are methyl.

Most preferred compounds of formula (I) are the compounds wherein:

R is aryl; R1 is selected from NHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl and an optionally further substituted straight or branched C₁-C₆ alkyl;

B is CR2, and A, D and E are CH;

R2 is selected from OR7, NR8R9, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl; Ra and Rb are methyl.

Specific compounds (cpd.) of the invention are listed below:

-   1. (S)-Tetrahydro-furan-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   2. (R)-Tetrahydro-furan-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   3. Piperidine-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   4. Piperidine-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   5. Piperidine-4-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   6. Tetrahydro-furan-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   7. Tetrahydro-pyran-4-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   8. Tetrahydro-pyran-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   9. Tetrahydro-pyran-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   10. 1H-Pyrrole-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   11. 1H-Pyrrole-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   12. 1-Methyl-1H-pyrrole-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   13. 1-Methyl-1H-pyrrole-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   14. 3H-Imidazole-4-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   15. 3-Methyl-3H-imidazole-4-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   16. 1-Methyl-1H-imidazole-4-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   17. 1H-Imidazole-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   18. 1-Methyl-1H-imidazole-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   19. Pyridine-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   20.     N-[2-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-nicotinamide; -   21.     N-[2-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-isonicotinamide; -   22.     2-Benzoylamino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide; -   23. 5-Methyl-isoxazole-4-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   24. Thiophene-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   25. Thiophene-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   26. Furan-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   27. Furan-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   28. 2H-Pyrazole-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   29. 2-Methyl-2H-pyrazole-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   30. 1-Methyl-1H-pyrazole-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   31. 5-Methyl-2H-pyrazole-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   32. 1H-Pyrazole-4-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   33. 1-Methyl-1H-pyrazole-4-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   34. Thiazole-4-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   35. 3-Methyl-thiophene-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   36. 1H-Pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide; -   37. 1H-Pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide; -   38. 1H-Pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide; -   39. 1H-Pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-fluoro-phenyl}-amide; -   40. 1H-Pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide; -   41. 1H-Pyrrole-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(2-dimethylamino-ethoxy)-phenyl]-amide; -   42. 1H-Pyrrole-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide; -   43. 1H-Pyrrole-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-azetidin-3-yloxy)-phenyl]-amide; -   44. 1H-Pyrrole-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-piperidin-4-yloxy)-phenyl]-amide; -   45. 1H-Pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-amide; -   46. 1H-Pyrrole-3-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide; -   47. 1H-Pyrrole-3-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide; -   48. 1H-Pyrrole-3-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide; -   49. 1H-Pyrrole-3-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-amide; -   50. 1H-Pyrrole-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(2-dimethylamino-ethoxy)-phenyl]-amide; -   51. 1H-Pyrrole-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-azetidin-3-yloxy)-phenyl]-amide; -   52. 1H-Pyrrole-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-piperidin-4-yloxy)-phenyl]-amide; -   53. 1H-Pyrrole-3-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide; -   54. 1H-Pyrrole-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide; -   55. (S)-1-Methyl-pyrrolidine-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide; -   56. (S)-1-Methyl-pyrrolidine-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide; -   57. 1H-Imidazole-4-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide; -   58. 1-Methyl-1H-pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide; -   59. 1-Methyl-1H-pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide; -   60. 1-Methyl-1H-pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide; -   61. 1-Methyl-1H-pyrrole-2-carboxylic acid [2-[5-(3,5-difluoro-benz     enesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(2-dimethylamino-ethoxy)-phenyl]-amide; -   62. 1-Methyl-1H-pyrrole-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide; -   63. 1-Methyl-1H-pyrrole-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-azetidin-3-yloxy)-phenyl]-amide; -   64. 1-Methyl-1H-pyrrole-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-piperidin-4-yloxy)-phenyl]-amide; -   65. 1-Methyl-1H-pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-amide; -   66. 1-Methyl-1H-pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide; -   67.     2-[(3-Pyrrolidin-1-ylmethyl-benzoyl)amino]-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide; -   68. Tetrahydro-pyran-4-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide;

69. Tetrahydro-pyran-4-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide;

-   70. Tetrahydro-pyran-4-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide; -   71. Tetrahydro-pyran-4-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-amide; -   72. Tetrahydro-pyran-4-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(2-dimethylamino-ethoxy)-phenyl]-amide; -   73. Tetrahydro-pyran-4-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-azetidin-3-yloxy)-phenyl]-amide; -   74. Tetrahydro-pyran-4-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-piperidin-4-yloxy)-phenyl]-amide; -   75. Pyridine-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide; -   76.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[((S)-1-pyrrolidin-2-ylmethyl)-amino]-benzamide; -   77.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-morpholin-4-yl-2-[(((R)-1-pyrrolidin-2-ylmethyl)-amino]-benzamide; -   78.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   79.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-dimethylamino-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   80.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-morpholin-4-yl-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   81.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-methoxy-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   82.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(2-dimethylamino-ethoxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   83.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(2-pyrrolidin-1-yl-ethoxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   84.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(1-methyl-azetidin-3-yloxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   85.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(1-methyl-piperidin-4-yloxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   86.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   87.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(((R)-1-methyl-pyrrolidin-2-ylmethyl)-amino]-4-morpholin-4-yl-benzamide; -   88.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(piperidin-3-ylmethyl)-amino]-benzamide; -   89.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-phenylamino-benzamide; -   90.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-isobutylamino-4-(4-methyl-piperazin-1-yl)-benzamide; -   91.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[((R)-1-pyrrolidin-2-ylmethyl)-amino]-benzamide; -   92.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[((S)-1-pyrrolidin-2-ylmethyl)-amino]-benzamide; -   93.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(furan-2-ylmethyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzamide; -   94.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(1H-imidazol-2-ylmethyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzamide; -   95.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   96.     2-Benzylamino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide; -   97.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-thiopyran-4-ylamino)-benzamide; -   98.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(piperidin-4-ylamino)-benzamide; -   99.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(4-hydroxy-b     enzylamino)-4-(4-methyl-piperazin-1-yl)-benzamide; -   100.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[((R)-1-methyl-pyrrolidin-2-ylmethyl)-amino]-benzamide; -   101.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-hydroxy-b     enzylamino)-4-(4-methyl-piperazin-1-yl)-benzamide; -   102. 1H-Pyrrole-2-carboxylic acid     [2-(5-benzenesulfonyl-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl)-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   103. 1H-Pyrrole-2-carboxylic acid     [2-[5-(3-fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   104.     N-[5-(3-Fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   105. 1-Methyl-1H-pyrrole-2-carboxylic acid     [2-[5-(3-fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   106. 1H-Pyrrole-3-carboxylic acid     [2-[5-(3-fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   107. Tetrahydro-pyran-4-carboxylic acid     [2-[5-(3-fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   108. Tetrahydro-furan-2-carboxylic acid     [2-[5-(3-fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   109.     N-[5-(2-Fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   110.     N-[5-(3,5-Dichloro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   111.     N-[5-(3-Chloro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   112.     N-[6,6-Dimethyl-5-(thiophene-2-sulfonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   113.     N-[5-(2,6-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   114.     N-[6,6-Dimethyl-5-(pyridine-3-sulfonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   115. N-[5-(3-Methoxy-benz     enesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   116.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-3-[(1H-pyrrole-2-carbonyl)-amino]-isonicotinamide; -   117.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-3-(tetrahydro-pyran-4-ylamino)-isonicotinamide; -   118.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(4-hydroxy-cyclohexylamino)-nicotinamide; -   119.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-nicotinamide; -   120.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(1H-pyrrole-2-carbonyl)-amino]-nicotinamide; -   121. 3-(Tetrahydro-pyran-4-ylamino)-pyridine-2-carboxylic acid     [5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-amide; -   122. 3-[(1H-Pyrrole-2-carbonyl)-amino]-pyridine-2-carboxylic acid     [5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-amide; -   123. 1H-Pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-3-fluoro-phenyl}-amide; -   124.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-(tetrahydro-pyran-4-ylamino)-benzamide; -   125. 1H-Pyrrole-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-3-fluoro-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   126.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-4-(4-methyl-piperazin-1-yl)-6-(tetrahydro-pyran-4-ylamino)-benzamide; -   127.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3-ethyl-ureido)-4-(4-methyl-piperazin-1-yl)-benzamide; -   128.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3,3-dimethyl-ureido)-4-(4-methyl-piperazin-1-yl)-benzamide; -   129. Pyrrolidine-1-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   130. Morpholine-4-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   131. 1H-Pyrrole-2-carboxylic acid     [2-(5-benzenesulfonyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl)-phenyl]-amide; -   132.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-dimethylaminomethyl-6-fluoro-benz     amide; -   133.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-(isopropylamino-methyl)-benzamide; -   134.     2-Cyclopentylaminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-6-fluoro-benzamide; -   135.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-[(tetrahydro-pyran-4-ylamino)-methyl]-benzamide; -   136.     2-Cyclobutylaminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-6-fluoro-benzamide; -   137.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-morpholin-4-ylmethyl-benzamide; -   138.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-dimethylaminomethyl-benzamide; -   139.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(isopropylamino-methyl)-benzamide; -   140.     2-Cyclopentylaminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide; -   141.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(tetrahydro-pyran-4-ylamino)-methyl]-benzamide; -   142.     2-Cyclobutylaminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide; -   143.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-morpholin-4-ylmethyl-benz     amide; -   144. Tetrahydro-furan-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   145.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-dimethylamino-acetylamino)-benzamide; -   146.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-methylamino-acetylamino)-benzamide; -   147. (S)-Pyrrolidine-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide; -   148. (S)-Pyrrolidine-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide; -   149.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(tetrahydro-furan-2-ylmethyl)-amino]-nicotinamide; -   150.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3-hydroxy-propylamino)-nicotinamide; -   151.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(4-methoxy-benzylamino)-nicotinamide; -   152.     2-Chloro-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-nicotinamide; -   153.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-nicotinamide; -   154.     2,6-Dichloro-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-nicotinamide; -   155.     6-Chloro-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2,4-dimethoxy-benzylamino)-nicotinamide; -   156.     6-Chloro-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2,4-dimethoxy-benzylamino)-nicotinamide; -   157.     6-Chloro-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-nicotinamide; -   158.     2-Amino-6-chloro-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-nicotinamide; -   159.     2-Chloro-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-6-morpholin-4-yl-nicotinamide; -   160.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2,4-dimethoxy-benzylamino)-6-morpholin-4-yl-nicotinamide; -   161.     2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-nicotinamide; -   162.     N-{5-[3-Fluoro-5-(3-hydroxy-propylamino)-benzenesulfonyl]-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl}-2-(3-hydroxy-propylamino)-nicotinamide; -   163.     2-Aminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-6-fluoro-benzamide; -   164.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide; -   165.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide; -   166.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide; -   167.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide; -   168.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide; -   169.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3-methoxy-1-methyl-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide; -   170.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((R)-3-methoxy-1-methyl-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide; -   171.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((S)-3-methoxy-1-methyl-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide     and -   172.     N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide.

Preferred specific compounds (cpd.) of the invention are listed below:

-   (S)-Tetrahydro-furan-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   Tetrahydro-pyran-4-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   1H-Pyrrole-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   1H-Pyrrole-3-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   1-Methyl-1H-pyrrole-2-carboxylic acid     [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; -   1H-Pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide; -   1H-Pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide; -   1H-Pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide; -   1H-Pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide; -   1H-Pyrrole-3-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide; -   1H-Pyrrole-3-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide; -   1-Methyl-1H-pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide; -   Tetrahydro-pyran-4-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide; -   Tetrahydro-pyran-4-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide; -   N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-dimethylamino-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-morpholin-4-yl-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   1H-Pyrrole-2-carboxylic acid     {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-3-fluoro-phenyl}-amide; -   N-[5-(3-Chloro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   N-[5-(3-Fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; -   N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide; -   N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide     and -   N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide.

The present invention also provides a process for the preparation of a compound of formula (I) defined as above; which process comprises:

a) reacting a compound of formula (II)

wherein Ra and Rb are as defined above, Q is a lower alkyl group, for instance a C₁-C₄ alkyl group, more preferably methyl or ethyl, with a compound of formula (III)

wherein R1 and A, B, D, E are as defined above and Z is hydroxy, halogen or a suitable leaving group; b) deprotecting the resulting compound of formula (IV),

wherein R1, A, B, D, E, Ra, Rb, and Q are as defined above, under acidic conditions; c) reacting the resulting compound of formula (V),

wherein R1, A, B, D, E, Ra, Rb, and Q are as defined above, with a compound of formula (VI),

wherein Z and R are as defined above so as to obtain a compound of formula (VII),

wherein R, R1, A, B, D, E, Ra, Rb, and Q are as defined above and optionally converting it into another compound of formula (VII); d) deprotecting the compound of formula (VII) as defined above under basic conditions so as to obtain the corresponding compound of formula (I), which can be further separated into the single isomers when it contains one or more asymmetric centers, and optionally converting it into another compound of formula (I) and/or into a pharmaceutically acceptable salt if desired.

It is to be noted that a compound of formula (II), (IV), (V) and (VII) as above defined can be in any one of its isomeric forms a or b:

As said above, a compound of formula (VII) may be converted into another compound of formula (VII), the following being examples of possible conversions:

1) preparation of a compound of formula (VII), wherein R1 is amino by reducing a compound of formula (VII), wherein R1 is nitro; 2) preparation of a compound of formula (VII), wherein R1 is NHCOR4 by reacting a compound of formula (VII), wherein R1 is amino with a compound of formula (VIII),

wherein R4 and Z are as defined above; 3) preparation of a compound of formula (VII), wherein R1 is NHCONHR8 by reacting a compound of formula (VII), wherein R1 is amino with an isocyanate of formula (IX),

R8-N═C═O  (IX)

wherein R8 is as defined above; 4) preparation of a compound of formula (VII), wherein R1 is NHSO₂R10, and R, A, B, D, E, Ra, Rb, R10 and Q are as defined above, reacting a compound of formula (VII), wherein R1 is amino and R, A, B, D, E, Ra, Rb and Q are as defined above, with a compound of formula (X),

wherein R10 and Z are as defined above; 5) preparation of a compound of formula (VII), wherein R1 is a NR5R6 group, wherein one of the R5 or R6 is hydrogen and the other is an optionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl, R8R9N—C₂-C₆ alkyl, R7O—C₂-C₆ alkyl, wherein R7, R8 and R9 are as defined above, by reacting a compound of formula (VII), wherein R1 is amino with a suitable aldehyde or ketone in presence of a reducing agent.

As said above, a compound of formula (I) may be converted into another compound of formula (I), the following being an example of possible conversions:

a compound of formula (I), wherein R1 is amino may be converted into a compound of formula (I) wherein R1 is NR5R6, wherein R5 and R6 are defined as in conversion 5), by reacting it with a suitable aldeyde or ketone in presence of a reducing agent.

The synthesis of a compound of formula (I), according to the synthetic process described above, can be conducted in a stepwise manner, whereby each intermediate is isolated and purified by standard purification techniques, like, for example, column chromatography, before carrying out the subsequent reaction. Alternatively, two or more steps of the synthetic sequence can be carried out in a so-called “one-pot” procedure, as known in the art, whereby only the compound resulting from the two or more steps is isolated and purified.

According to step a) of the process, the reaction between a compound of formula (II) and a compound of formula (III) can be carried out in a variety of ways, according to conventional methods for acylating amino derivatives. As an example, a compound of formula (II) may be reacted with an acyl chloride of formula (III), in which case Z represents a chlorine atom. Preferably, this reaction is carried out in a suitable solvent such as, for instance, tetrahydrofuran, dichloromethane, toluene, 1,4-dioxane, acetonitrile and in presence of a proton scavenger such as, for example, triethylamine, N,N-diisopropylethylamine, pyridine, at a temperature ranging from room temperature to reflux, for a time ranging from about 30 min. to about 96 hours. It is known to the skilled person that when a compound of formula (III) carries functional groups that may interfere with the above reaction, such groups have to be protected before carrying out the reaction. In particular, when a compound of formula (III) is substituted by residues of general formula NR5R6, OR7, or R8R9N—C₁-C₆ alkyl, wherein R7 or one or both of R5 and R6, or R8 and R9 represent hydrogen, such groups are protected as known in the art. Introduction of a nitrogen protecting group may also be required for a compound of formula (III), wherein R1 is NHCOR7 or NHSO₂R10. It is also known to the skilled person that such protecting group may be removed just after the reaction of a compound of formula (III) with a compound of formula (II) or at a later stage in the synthetic process. Removal of some protective groups may also affect the pyrazole protecting group (—COOQ) of a compound of formula (IV) or (VII). If needed, such pyrazole protecting group can be reinstalled at a later stage in the synthetic process.

According to step b) of the process, a compound of formula (IV) is easily deprotected at the dihydropyrrole nitrogen atom by acidic treatment. This reaction can be conveniently carried out in presence of an inorganic or organic acid such as, for instance, hydrochloric, trifluoroacetic or methanesulfonic acid, in a suitable solvent such as dichloromethane, 1,4-dioxane, a lower alcohol, such as methanol or ethanol, at a temperature ranging from room temperature to about 40° C. and for a period of time varying from about 1 hour to about 48 hours.

The compound of formula (V) thus obtained is further reacted, according to step c) of the process, with a compound of formula (VI). From the above it is clear to the skilled person that this sulfonylation reaction may be accomplished in a variety of ways and experimental conditions, which are widely known in the art for the preparation of sulfonamides. As an example, the reaction between a compound of formula (V) and a sulfonyl chloride of formula (VI), in which case Z is a chlorine atom, can be carried out in a suitable solvent such as, for instance, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, toluene, 1,4-dioxane, acetonitrile and in presence of a proton scavenger such as, for instance, triethylamine, N,N-diisopropylethylamine, pyridine, at a temperature ranging from about −10° C. to reflux, and for a period of time ranging, for instance, from about 30 min to about 96 hours.

According to step d) of the process, a compound of formula (VII) is transformed into a compound of formula (I) by deprotection of the pyrazole nitrogen atom by working according to conventional methods enabling the selective hydrolysis of a carbamate protecting group. As an example, this reaction may be carried out under basic conditions, for instance in presence of sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide, or of a tertiary amine such as triethylamine, or of hydrazine, and in a suitable solvent such as methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, water and mixtures thereof. Typically, the reaction is carried out at a temperature ranging from room temperature to about 60° C. and for a time varying from about 30 minutes to about 96 hours.

According to the conversion described in 1) the reduction of a compound of formula (VII), wherein R1 is nitro, to a compound of formula (VII) wherein R1 is amino can be carried out in a variety of ways, according to conventional methods for reducing a nitro to an amino group. Preferably, this reaction is carried out in a suitable solvent such as, for instance, methanol, ethanol, water, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, acetic acid, or a mixture thereof, in presence of a suitable reducing agent, such as, for instance, hydrogen and a hydrogenation catalyst, or by treatment with cyclohexene or cyclohexadiene, or formic acid or ammonium formate and a hydrogenation catalyst, or a metal such as iron or zinc in presence of an inorganic acid, such as hydrochloric acid, or by treatment with tin (II) chloride, at a temperature ranging from 0° C. to reflux and for a time varying from about 1 hour to about 96 hours. The hydrogenation catalyst is usually a metal, most often palladium, which can be used as such or supported on carbon.

According to the conversion described in 2) the acylation of a compound of formula (VII), wherein R1 is amino, can be accomplished in a variety of ways and experimental conditions, which are widely known in the art for the preparation of carboxamides. As an example, the reaction between a compound of formula (VII) and a carboxylic acid derivative of formula (VIII), wherein Z is as defined above, can be carried out in presence of a tertiary base, such as triethylamine, N,N-diisopropylethylamine or pyridine, in a suitable solvent, such as toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, or N,N-dimethylformamide, at a temperature ranging from about −10° C. to reflux and for a period of time varying from about 1 hour to about 96 hours.

According to the conversion described in 3) the reaction of a compound of formula (VII), wherein R1 is amino with an isocyanate of formula (IX), may be carried out in a solvent such as toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 1,4-dioxane, or acetonitrile at a temperature ranging from about −10° C. to reflux and for a period of time varying from about 1 hour to about 96 hours.

According to the conversion described in 4) the reaction of a compound of formula (VII), wherein R1 is amino with a compound of formula (X) may be accomplished in a variety of ways and experimental conditions which are widely known in the art for the preparation of sulfonamides. As an example, the reaction between a compound of formula (VII) and a sulfonyl chloride of formula (X), in which case Z is a chlorine atom, can be carried out in a suitable solvent such as, for instance, diethyl ether, tetrahydrofuran, dichloromethane, chloroform, toluene, 1,4-dioxane, acetonitrile and in presence of a proton scavenger such as triethylamine, N,N-diisopropylethylamine, pyridine, at a temperature ranging from about −10° C. to reflux, and for a period of time ranging, for instance, from about 30 min to about 96 hours.

According to the conversion described in 5) the reaction of a compound of formula (VII), wherein R1 is amino, with an aldehyde or a ketone, can be conducted in a variety of ways, according to conventional methods for carrying out reductive alkylation. Preferably, this reaction is carried out in a suitable solvent such as, for instance, methanol, N,N-dimethylformamide, dichloromethane, tetrahydrofuran, or a mixture thereof, in presence of a suitable reducing agent such as, for instance, sodium borohydride, tetra-alkylammonium borohydride, sodium cyano borohydride, sodium triacetoxyborohydride, tetramethylammonium triacetoxy borohydride, hydrogen and a hydrogenation catalyst, such as for instance nickel or platinum or palladium, and in presence of an acid catalyst, such as, for instance, acetic acid or trifluoroacetic acid, at a temperature ranging from about 0° C. to reflux and for a time varying from about 1 hour to about 96 hours.

A compound of formula (I) can be converted into another compound of formula (I) in a way analogous to that specified above under 5).

The deprotection of a compound of formula (VII) wherein R1 is a protected amino group, can be made in a variety of ways according to conventional methods for deprotecting amino groups. Depending on the amino protecting group, this reaction can be conducted in different ways. In one aspect, such reaction can be carried out by treatment of a compound of formula (VII) with an inorganic acid, such as hydrochloric, sulphuric or perchloric acid, or an organic acid, such as trifluoroacetic or methanesulfonic acid, in a suitable solvent, such as water, methanol, ethanol, 1,4-dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, acetonitrile, N,N-dimethylformamide, dichlorometane or mixtures thereof, at a temperature ranging from −10° C. to 80° C., and for a period of time ranging from 30 minutes to 48 hours. In another aspect, such reaction can be carried out by treatment of a compound of formula (VII) with an inorganic base, such as lithium or sodium or potassium hydroxide, or sodium or potassium or caesium carbonate, or with an organic base, such as triethylamine or N,N-diisopropylethylamine, or with anhydrous hydrazine or hydrazine hydrate in a suitable solvent such as water, methanol, ethanol, 1,4-dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether, acetonitrile, N,N-dimethylformamide, dichloromethane or mixtures thereof, at a temperature ranging from −10° C. to 80° C., and for a period of time ranging from 30 minutes to 72 hours. In still another option, such reaction can be carried out by treatment of a compound of formula (VII) with hydrogen or cyclohexene or cyclohexadiene and a hydrogenation catalyst, such as palladium on carbon, or with a metal, such as zinc, and an inorganic or organic acid, such as hydrochloric or acetic acid, in a suitable solvent such as water, methanol, ethanol, 1,4-dioxane, tetrahydrofuran or mixture thereof, at a temperature ranging from −10° C. to 80° C., and for a period of time ranging from 30 minutes to 72 hours.

Substituted pyrrolo[3,4-c]pyrazole derivatives can be prepared using standard procedures in organic synthesis as reported, for instance, in Smith, Michael—March's Advanced Organic Chemistry: reactions mechanisms and structure—5^(th) Edition, Michael B. Smith and Jerry March, John Wiley & Sons Inc., New York (NY), 2001. It is known to the skilled person that transformation of a chemical function into another may require that one or more reactive centers in the compound containing this function be protected in order to avoid undesired side reactions. Protection of such reactive centers, and subsequent deprotection at the end of the synthetic transformations, can be accomplished following standard procedures described, for instance, in: Green, Theodora W. and Wuts, Peter G. M.—Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons Inc., New York (NY), 1999.

In cases where a compound of formula (I) contains one or more asymmetric centers, said compound can be separated into the single isomers by procedures known to those skilled in the art. Such procedures comprise standard chromatographic techniques, including chromatography using a chiral stationary phase, or crystallization. General methods for separation of compounds containing one or more asymmetric centers are reported, for instance, in Jacques, Jean; Collet, André; Wilen, Samuel H.,—Enantiomers, Racemates, and Resolutions, John Wiley & Sons Inc., New York (NY), 1981.

A compound of formula (I) can also be transformed into a pharmaceutically acceptable salt according to standard procedures that are known to those skilled in the art. Alternatively, a compound of formula (I) that is obtained as a salt can be transformed into the free base or the free acid according to standard procedures that are known to the skilled person.

The starting materials of the process of the present invention are either known or can be prepared according to known methods. As an example, the preparation of a compound of formula (II), wherein Q represents ethyl and Ra and Rb are methyl, is disclosed in the international application WO 04/056827 (see, in particular, example 6 at page 50; this same compound is therein named as 5-tert-butyl-1-ethyl-3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate). Additional compounds of formula (II), wherein Q represents a lower alkyl group other than ethyl, can be prepared by applying procedures similar to those disclosed in the above mentioned patent application. The desired isomeric form of compounds of formula (II) may be obtained by separation of the mixture of isomers by methods known in the art.

The compounds of formula (III) and (VIII), for instance those wherein Z represents a halogen atom, e.g. a chlorine atom, are either known or can be easily obtained from the corresponding carboxylic acids, that are either known or can be prepared by working according to conventional synthetic methods. The compounds of formula (VI) and (X), for instance those wherein Z represents a halogen atom, e.g. a chlorine atom, are either known or can be prepared from sulfonic acids according to conventional synthetic methods. The compounds of formula (IX) are either known or can be synthesized according to conventional synthetic methods for the preparation of isocianates such as, for instance, treatment of an amine with triphosgene.

PHARMACOLOGY

The short forms and abbreviations used herein have the following meaning:

Ci Curie

DMSO dimethylsulfoxide KDa kiloDalton microCi microCurie mg milligram microg microgram mL milliliter microL microliter M molar mM millimolar microM micromolar nM nanomolar

Assays

Compounds of the present invention were tested in biochemical as well as in cell-based assays, as described below.

Preparation of IGF-1R for Use in Biochemical Assay Cloning and Expression

Human cDNA was used as template for amplification by polymerase chain reaction (PCR) of the predicted cytoplasmic portion of IGF-1R (amino acid residues 960-1367 of precursor protein; see NCBI Entrez Protein Accession #P08069), which includes the entire kinase domain. PCR was conducted using the forward primer sequence 5′-CTCGGATCCAGAAAGAGAAATAACAGCAGGCTG-3′ and the reverse primer sequence 5′-CTCGGATCCTCAGCAGGTCGAAGACTGGGGCAGCGG-3′. In order to facilitate subsequent cloning steps, both primers comprise a BamHI restriction endonuclease site sequence. This PCR product was cloned in frame using BamHI sticky ends into a transfer vector for the baculovirus expression system, pVL1392 (Pharmingen), previously modified by insertion into the pVL1392 multiple cloning site of sequences encoding Glutathione S-transferase (GST) fusion protein, PreScission protease cleavage site and partial MCS cassette derived from the pGex-6P plasmid (Amersham BioSciences). Insertion of the IGF-1R PCR product described above into the pGex-6P derived BamHI site of the modified pVL1392 vector results in an open reading frame corresponding to the pGEX-6P GST protein and PreScission peptide fused with the human IGF-1R cytoplasmic domain. In order to obtain fusion protein, Sf21 insect cells (Invitrogen) are cotransfected with 2 microg of purified plasmid and 1 microg of virus DNA (BaculoGold™ Transfection Kit, Pharmingen), as described in the Baculovirus Instruction manual (Pharmingen). A first amplification of the virus is performed using 600 microL of cotransfected virus on 6×10⁶ Sf21 in a monolayer culture, in 12 mL of medium (TNM-FH Grace's medium—Pharmingen). After 3 days the medium is collected, centrifuged and transferred to a sterile tube. A second amplification is prepared with the same method using 2 mL on 3×10⁷ cells, diluted in 40 mL of medium. For the third amplification of virus, 1 mL of supernatant from the second round are used per 3×10⁷ cells diluted in 40 mL of medium.

Protein expression is performed in H5 insect cells infected with 14 mL virus/1×10⁹ insect cells (MOI=1.5) for 65 h with shaking at 27° C. Cells are harvested by centrifugation at 1200×g for 10 minutes.

Protein Purification

Cells were resuspended in phosphate buffered saline solution (PBS), 20 mM dithiothreitol (DTT), 0.2% CHAPS, 20% glycerol, 1 mM OVA, “Complete” protease inhibitor cocktail (1 tablet/50 mL buffer; Roche Diagnostics, Milan, Italy) and lysed by liquid extrusion with a Gaulin homogenizer (Niro Soavi, Italy). The lysate was centrifuged at 14000×g for 45 minutes and the supernatant was loaded onto a column containing 10 mL Glutathione Sepharose (Amersham Biosciences). The column was first washed with PBS buffer for 5 column volumes, then with 100 mM Tris pH 8.0, 20% glycerol for 5 column volumes, and lastly eluted with 10 mM glutathione in 100 mM Tris pH 8.0, 20% glycerol. Fractions of 10 mL were collected, and protein-rich fractions were pooled. Typically, 20 mg of fusion protein were recovered from 1×10⁹ cells, and this was typically >85% pure as judged by SDS-PAGE followed by Coomassie staining. Purified protein was stored at −80° C. prior to its use in biochemical assays.

Biochemical Assay for Inhibitors of IGF-1R Kinase Activity

The inhibitory activity of putative kinase inhibitors and the potency of selected compounds were determined using a trans-phosphorylation assay.

A specific substrate was incubated with the kinase in appropriate buffer conditions in presence of ATP traced with ³³P-γ-ATP (gamma phosphate-labeled, Redivue™ Code Number AH9968, 1000-3000 Ci/mmole, Amersham Biosciences Piscataway, N.J., USA), optimal cofactors and test compound.

At the end of the phosphorylation reaction, more than 98% cold and radioactive ATP were captured by an excess of Dowex ion exchange resin. The resin was allowed to settle to the bottom of reaction wells by gravity. Supernatant, containing substrate peptide, was subsequently withdrawn and transferred into a counting plate, and radioactivity (corresponding to phosphate incorporated into peptide) was evaluated by β-counting.

Reagents/Assay Conditions

i. Dowex Resin Preparation

500 g of wet resin (SIGMA, custom prepared DOWEX resin 1×8 200-400 mesh, 2.5 Kg) were weighed out and diluted to 2 L in 150 mM sodium formate, pH 3.00.

The resin was allowed to settle for several hours and then the supernatant was discarded. This washing procedure was repeated three times over two days. Finally, the resin was allowed to settle, supernatant was discarded and two volumes (with respect to the resin volume) of 150 mM sodium formate buffer were added. The final pH was circa 3.0. The washed resin was kept at 4° C. before use, and was stable for more than one week.

ii. Kinase Buffer (KB)

Kinase buffer was composed of 50 mM HEPES pH 7.9 containing 3 mM MnCl₂, 1 mM DTT, 3 microM Na₃VO₄, and 0.2 mg/mL BSA. 3×KB is buffer of the same composition and pH as KB, but with three times the concentration of each component.

iii. Enzyme Pre-Activation and Preparation of 3× Enzyme Mix.

Prior to starting the kinase inhibition assay, IGF-1R was pre-phosphorylated in order to linearize reaction kinetics. To achieve this, the desired total quantity of enzyme was prepared at an enzyme concentration of 360 nM in KB containing 100 microM ATP, and this preparation was incubated for 30 min at 28° C. 3× Enzyme Mix was obtained by diluting this preactivated enzyme 20-fold in 3×KB.

iv. Assay Conditions

The kinase assay was run with a final enzyme concentration of 6 nM, in presence of 6 microM ATP, 1 nM ³³P-γ-ATP and 10 microM substrate, a carboxy-terminally biotinylated peptide of the following sequence: KKKSPGEYVNIEFGGGGGK-biotin. The peptide was obtained in batches of >95% peptide purity from American Peptide Company, Inc. (Sunnyvale, Calif., USA).

Robotized Dowex Assay

Test reactions were performed in a total final volume of 21 microL consisting of:

a) 7 microL/well of 3× Enzyme Mix (18 nM preactivated enzyme in 3× kinase buffer), b) 7 microL/well of 3× substrate/ATP mix (30 microM substrate, 18 microM ATP, 3 nM ³³P-γ-ATP in double-distilled water (ddH₂O)), c) 7 microL/well 3× test compounds diluted into ddH₂O-3% DMSO. Compound dilution and assay scheme is reported below. i. Dilution of Compounds

10 mM stock solutions of test compounds in 100% DMSO were distributed into 96 well 12×8 format microtiter plates.

For % inhibition studies, dilution plates at 1 mM, 100 microM and 10 microM were prepared in 100% DMSO, then diluted to 3× final desired concentration (30, 3 and 0.3 microM) in ddH₂O, 3% DMSO. A Multimek 96 (Beckman Coulter, Inc. 4300 N. Harbor Boulevard, P.O. Box 3100 Fullerton, Calif. 92834-3100 USA) was used for compound pipetting into test plates.

For IC₅₀ determination, starting solutions of 30 microM compound in 3% DMSO were derived from 1 mM/100% DMSO stock solutions. These 30 microM starting solutions were used for generation of a further 9 serial ⅓ dilutions in ddH₂O, 3% DMSO, so as to generate a 10-point dilution curve at 3× the final assay concentration. Serial dilution was conducted in 96-well plates using a Biomek 2000 (Beckman Coulter) system. Dilution curves of 7 compounds/plate were prepared, and each plate also included a 10-point dilution curve of Staurosporine, as well as several negative and positive control wells.

ii. Assay Scheme

7 microL of each test compound dilution (or control) in ddH₂O, 3% DMSO were pipetted into each well of a 384-well, V-bottom assay plate, which was then transferred to a PlateTrak 12 robotized station (Perkin Elmer, 45 William Street Wellesley, Mass. 02481-4078, USA) equipped with one 384-tip pipetting head for starting the assay, plus one 96-tip head for dispensing the resin) prepared with reservoirs containing sufficient 3× Enzyme mix and 3×ATP mix (3×) to complete the assay run.

At the start of the assay the liquid handling system aspirates 7 microL of ATP mix, introduces an air gap inside the tips (5 microL) and then aspirates 7 microL of 3× Enzyme Mix. To start the reaction, tips contents were dispensed into the test wells already containing 7 microL test compound (at 3× desired final concentration), followed by 3 cycles of mixing, so as to restore desired final concentration for all reaction components.

Plates were incubated for 60 minutes at room temperature, and then the reaction was stopped by pipetting 70 microL of Dowex resin suspension into the reaction mix, followed by three cycles of mixing. After stopping the reaction, plates were allowed to rest for one hour in order to maximize ATP capture. At this point, 20 microL of supernatant were transferred from each well into wells of 384-Optiplates (Perkin Elmer) containing 70 microL/well of Microscint 40 (Perkin Elmer); after 5 min of orbital shaking the plates were read on a Perkin-Elmer Top Count radioactivity counter.

iii. Data Analysis

Data were analysed using a customized version of the “Assay Explorer” software package (Elsevier MDL, San Leandro, Calif. 94577). For single compound concentrations, inhibitory activity was typically expressed as % inhibition obtained in presence of compound, compared to total activity of enzyme obtained when inhibitor is omitted. Compounds showing desired inhibition were further analysed in order to study the potency of the inhibitor through IC₅₀ calculation. In this case, inhibition data obtained using serial dilutions of the inhibitor were fitted by non-linear regression using the following equation:

$\mspace{79mu} {v = {v_{0} + \frac{\text{?} - {v_{b}\text{?}}}{1 + 10^{{n\text{?}{IC}_{50}} - {\log \text{?}}}}}}$ ?indicates text missing or illegible when filed

where ν_(b) is the baseline velocity, ν is the observed reaction velocity, ν_(o) is the velocity in the absence of inhibitors, and [I] is the inhibitor concentration.

Cell-Based Assays for Inhibitors of IGF-1R Kinase Activity

Western Blot Analysis of Receptor Phosphorylation Following Stimulation with IGF-1 in MCF-7 Human Breast Cancer Cells

MCF-7 cells (ATCC# HTB-22) were seeded in 12-well tissue culture plates at 2×10⁵ cells/well in E-MEM medium (MEM+Earle's BSS+2 mM glutamine+0.1 mM non-essential amino acids)+10% FCS, and incubated overnight at 37° C., 5% CO2, 100% relative humidity. Cells were then starved by replacing E-MEM+10% FCS with E-MEM+0.1% BSA, and incubating overnight. After this incubation, wells were treated with desired concentrations of compound for 1 hour at 37° C., and were then stimulated with 10 nM recombinant human IGF-1 (Invitrogen, Carlsbad, Calif., USA) for 10 minutes at 37° C. Cells were then washed with PBS and lysed in 100 microL/well cell lysis buffer (M-PER Mammalian Protein Extraction Reagent [Product #78501, Pierce, Rockford, Ill., USA]+10 mM EDTA+Protease inhibitor cocktail [Sigma-Aldrich product #P8340]+phosphatase inhibitor cocktail [Sigma-Aldrich products #P2850+#P5726]). Cell lysates were cleared by centrifugation at 10,000×g for 5 minutes, and 10 microg/lane of cleared lysate protein were run on NuPAGE gels (NuPAGE 4-12% 10-lane Bis-Tris gels, Invitrogen) with MOPS running buffer, then transferred onto Hybond-ECL nitrocellulose filters (Amersham Biosciences, Little Chalfont, Buckinghamshire, UK) using Mini PROTEAN II chambers (Bio-Rad Laboratories, Hercules, Calif., USA). Filters bearing transferred protein were incubated for 1 hour in blocking buffer (TBS+5% BSA+0.15% Tween 20), and probed for 2 hours in the same buffer containing 1/1000 rabbit anti-phospho IGF-1R Tyr1131/InsR Tyr 1146 antibody (product #3021, Cell Signaling Technology, Beverly, Mass., USA) for the detection of phosphorylated IGF-1R, or 1/1000 dilution of rabbit IGF-Irβ(H-60) antibody (product #sc-9038, Santa Cruz Biotechnology, Inc., Santa Cruz, Calif., USA) for detecting total IGF-1R β chain. In either case, filters were then washed for 30 minutes with several changes of TBS+0.15% Tween 20, and incubated for 1 hour in washing buffer containing 1/5000 dilution of horseradish peroxidase conjugated anti-rabbit IgG (Amersham, product #NA934), then were washed again and developed using the ECL chemiluminescence system (Amersham) according to manufacturer's recommendations. Unless otherwise stated, reagents used were from Sigma-Aldrich, St. Louis, Mo., USA.

Growth Factor Induced S6 Ribosomal Protein Phosphorylation in Primary Human Fibroblasts.

Phosphorylation of S6 ribosomal protein in response to growth factor stimulation of normal human dermal fibroblasts (NHDF) was used to assess compound potency in inhibiting IGF-1 induced signal transduction in cells, and selectivity towards EGF and PDGF stimulus. NHDF cells obtained from PromoCell (Heidelberg, Germany), were maintained at 37° C. in a humidified atmosphere with 5% CO₂ in complete Fibroblast Growth Medium (PromoCell). For assay, NHDF were seeded in 384-well tissue culture plates (clear- and flat-bottomed black plates; Matrix Technologies Inc., Hudson, N.H., USA) at a density of 5000 cells/well in serum-free medium containing 0.1% bovine serum albumin (BSA) and incubated for 5 days. Starved cells were treated for 1 hour with desired doses of compounds and then stimulated for a further 2 hours with either 10 nM IGF-1 (Invitrogen Corp., CA, USA), 10 nM EGF (Gibco BRL, USA) or 1 nM PDGF-B/B (Roche Diagnostics GmbH, Germany). Cells were then fixed in PBS/3.7% paraformaldehyde for 20 minutes at room temperature, washed ×2 with PBS, and permeabilized with PBS/0.3% Triton X-100 for 15 minutes. Wells were then saturated with PBS/1% non-fat dry milk (Bio-Rad Laboratories, Hercules, Calif., USA) for 1 hour, and then probed for 1 hour at 37° C. with anti-phospho-S6 (Ser 235/236) antibody (Cell Signaling Technology, Beverly, Mass., USA, cat. #2211) at 1/200 dilution in PBS/1% milk/0.3% Tween 20. Wells were then washed twice with PBS, and incubated for 1 hour at 37° C. with PBS/1% milk/0.3% Tween 20+1 microg/mL DAPI (4,6-diamidino-2-phenylindole)+1/500 Goat anti-rabbit Cy5™-conjugated secondary antibody (Amersham Biosciences, Little Chalfont, Buckinghamshire, UK). Wells were then washed ×2 with PBS, and 40 microL PBS are left in each well for immunofluorescence analysis. Fluorescence images in the DAPI and Cy5™ channels were automatically acquired, stored and analysed using a Cellomics ArrayScan™ IV instrument (Cellomics, Pittsburgh, USA); the Cellomics Cytotoxicity Algorithm was used to quantify cytoplasmic fluorescence associated with phospho-S6 (Cy5™ signal parameter: “Mean Lyso Mass-pH”) for each cell in 10 fields/well, and eventually expressed as a mean population value. Unless otherwise stated, reagents were obtained from Sigma-Aldrich, St. Louis, Mo., USA.

Biochemical Assay for Inhibitors of Aurora-2 Kinase Activity

The in vitro kinase inhibition assay was conducted in the same way as described for IGF-1R. At variance with IGF-1R, Aurora-2 enzyme does not need pre-activation.

i. Kinase Buffer (KB) for Aurora-2

The kinase buffer was composed of 50 mM HEPES, pH 7.0, 10 mM MnCl₂, 1 mM DTT, 3 microM Na₃VO₄, and 0.2 mg/mL BSA.

ii. Assay Conditions for Aurora-2 (Final Concentrations)

The kinase assay was run with an enzyme concentration of 2.5 nM, 10 microM ATP, 1 nM ³³P-γ-ATP, and 8 microM substrate, composed of 4 LRRWSLG repeats.

In Vitro Cell Proliferation Assay for Inhibitors of Aurora-2 Kinase Activity

The human colon cancer cell line HCT-116 was seeded at 5000 cells/cm² in 24 wells plate (Costar) using F12 medium (Gibco) supplemented with 10% FCS (EuroClone, Italy) 2 mM L-glutamine and 1% penicillin/streptomycin and maintained at 37° C., 5% CO₂ and 96% relative humidity. The following day, plates were treated in duplicates with 5 mL of an appropriate dilution of compounds starting from a 10 mM stock in DMSO. Two untreated control wells were included in each plate. After 72 hours of treatment, medium was withdrawn and cells detached from each well using 0.5 mL of 0.05% (w/v) Trypsin, 0.02% (w/v) EDTA (Gibco). Samples were diluted with 9.5 mL of Isoton (Coulter) and counted using a Multisizer 3 cell counter (Beckman Coulter). Data were evaluated as percent of the control wells:

% of CTR=(Treated−Blank)/(Control−Blank).

IC₅₀ values were calculated by LSW/Data Analysis using Microsoft Excel sigmoidal curve fitting.

Biochemical and cell-based assay data for representative compounds are reported in Table 1.

TABLE 1 Inhibition of IGF1-induced IGF1R IC₅₀ (μM) S6 phosphorylation Compound Biochemical assay IC₅₀ (μM) 1 0.17 0.74 11 0.09 0.30 90 0.46 5.3

The same compounds were tested for inhibition of IGF1-induced IGF1R phosphorylation in MCF-7 cells and results are shown in FIG. 1.

The compounds of the present invention can be administered either as single agents or, alternatively, in combination with known anticancer treatments such as radiation therapy or chemotherapy regimen in combination with, for example, antihormonal agents such as antiestrogens, antiandrogens and aromatase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, agents that target microtubules, platin-based agents, alkylating agents, DNA damaging or intercalating agents, antineoplastic antimetabolites, other kinase inhibitors, other anti-angiogenic agents, inhibitors of kinesins, therapeutic monoclonal antibodies, inhibitors of mTOR, histone deacetylase inhibitors, farnesyl transferase inhibitors, and inhibitors of hypoxic response.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within the approved dosage range.

Compounds of formula (I) may be used sequentially with known anticancer agents when a combination formulation is inappropriate.

The compounds of formula (I) of the present invention, suitable for administration to a mammal, e.g., to humans, can be administered by the usual routes and the dosage level depends upon the age, weight, and conditions of the patient and administration route. For example, a suitable dosage adopted for oral administration of a compound of formula (I) may range from about 10 to about 500 mg per dose, from 1 to 5 times daily. The compounds of the invention can be administered in a variety of dosage forms, e.g., orally, in the form tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form suppositories; parenterally, e.g., intramuscularly, or through intravenous and/or intrathecal and/or intraspinal injection or infusion.

The present invention also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, which may be a carrier or a diluent.

The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a suitable pharmaceutical form.

For example, the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e.g., silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g., starches, arabic gum, gelatine methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents, e.g., starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. These pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.

The liquid dispersions for oral administration may be, e.g., syrups, emulsions and suspensions.

As an example the syrups may contain, as a carrier, saccharose or saccharose with glycerine and/or mannitol and sorbitol.

The suspensions and the emulsions may contain, as examples of carriers, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., sterile water, olive oil, ethyl oleate, glycols, e.g., propylene glycol and, if desired, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injections or infusions may contain, as a carrier, sterile water or preferably they may be in the form of sterile, aqueous, isotonic, saline solutions or they may contain propylene glycol as a carrier.

The suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

With the aim to better illustrate the present invention, without posing any limitation to it, the following examples are now given.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the inhibition of IGF1R auto-phosphorylation in MCF-7 starved cells stimulated with 10 nM IGF1 by compounds of formula (I), exemplified by compound 1, 11, and 90.

Treatment of starved MCF-7 cells with 10 nM IGF1 induced receptor auto-phosphorylation as shown by the appearance of a more intense band of phosphorylated IGF1R (pIGF1R). Incubation of cells with increasing concentrations of compound 1, 11, and 90 prior to treatment with IGF1 resulted in inhibition of IGF1-induced IGF1R auto-phosphorylation as shown by the disappearance of the band of phosphorylated IGF1R (pIGF1R).

EXPERIMENTAL SECTION General Purification and Analytical Methods

Flash Chromatography was performed on silica gel (Merck grade 9395, 60A). HPLC was performed on Waters X Terra RP 18 (4.6×50 mm, 3.5 μm) column using a Waters 2790 HPLC system equipped with a 996 Waters PDA detector and Micromass mod. ZQ single quadrupole mass spectrometer, equipped with an electrospray (ESI) ion source. Mobile phase A was ammonium acetate 5 mM buffer (pH 5.5 with acetic acid-acetonitrile 95:5), and Mobile phase B was water-acetonitrile (5:95). Gradient from 10 to 90% B in 8 minutes, hold 90% B 2 minutes. UV detection at 220 nm and 254 nm. Flow rate 1 mL/min. Injection volume 10 microL. Full scan, mass range from 100 to 800 amu. Capillary voltage was 2.5 KV; source temperature was 120° C.; cone was 10 V. Retention times (HPLC r.t.) are given in minutes at 220 nm or at 254 nm Mass are given as m/z ratio.

When necessary, compounds were purified by preparative HPLC on a Waters Symmetry C18 (19×50 mm, 5 um) column or on a Waters X Terra RP 18 (30×150 mm, 5 μm) column using a Waters preparative HPLC 600 equipped with a 996 Waters PDA detector and a Micromass mod. ZMD single quadrupole mass spectrometer, electron spray ionization, positive mode. Mobile phase A was water-0.01% trifluoroacetic acid, and mobile phase B was acetonitrile. Gradient from 10 to 90% B in 8 min, hold 90% B 2 min. Flow rate 20 mL/min. In alternative, mobile phase A was water-0.1% NH₃, and mobile phase B was acetonitrile. Gradient from 10 to 100% B in 8 min, hold 100% B 2 min. Flow rate 20 mL/min.

1H-NMR spectrometry was performed on a Mercury VX 400 operating at 400.45 MHz equipped with a 5 mm double resonance probe [1H (15N-31P) ID_PFG Varian].

Example 1 Preparation of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoic acid Step 1 Preparation of 4-fluoro-2-nitro-benzoic acid tert-butyl ester

A solution of 4-fluoro-2-nitro-benzoic acid (10 g, 54 mmol), di-tert-butyl-dicarbonate (2 eq., 23.6 g, 108 mmol) and 4-dimethylaminopyridine (0.3 eq., 1.98 g, 16.2 mmol) in tert-butanol (100 mL) and dichloromethane (100 mL) was stiffed at room temperature for about 20 hours. The reaction mixture was then diluted with ethyl acetate (500 mL), washed with 1N HCl (500 mL), water (500 mL), brine (500 mL), dried over sodium sulfate and evaporated to dryness. The title compound was obtained as pale yellow oil (quantitative) and it was used in the next step without further purification.

1H-NMR (400 MHz),

(ppm, DMSO-d₆): 8.04 (dd, J=8.47, 2.50 Hz, 1H) 7.95 (dd, J=8.66, 5.37 Hz, 1H) 7.71 (ddd, J=8.66, 8.17, 2.56 Hz, 1H) 1.51 (s, 9H).

Step 2 Preparation of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoic acid tert-butyl ester

A solution of 4-fluoro-2-nitro-benzoic acid tert-butyl ester (13 g, 54 mmol) and N-methyl-piperazine (17 mL) was stirred at room temperature for about 6 hours. The reaction mixture was then diluted with water (800 mL) and maintained under magnetic stirring for about 20 hours. The resulting solid was filtered, washed thoroughly with water and dried under vacuum at 40° C. The title compound was obtained as a yellow solid (16.4 g, 94% yield), and was used in the next step without any further purification.

1H-NMR (400 MHz).

(ppm, DMSO-d₆): 7.69 (d, J=8.90 Hz, 1H) 7.29 (d, J=2.56 Hz, 1H), 7.15 (dd, J1=8.90 Hz, J2=2.56 Hz, 1H), 3.37 (m, 4H), 2.44 (m, 4H), 1.46 (s, 9H).

Operating in an analogous way, and using the suitable amine, the following compounds were obtained:

4-morpholin-4-yl-2-nitro-benzoic acid tert-butyl ester

1H-NMR (400 MHz),

(ppm, DMSO-d₆): 7.71 (d, J=8.77 Hz, 1H), 7.31 (d, J=2.44 Hz, 1H), 7.17 (dd, J1=8.77 Hz, J2=2.44 Hz, 1H), 3.73 (m, 4H), 3.35 (m, 4H), 1.46 (s, 9H).

4-dimethylamino-2-nitro-benzoic acid tert-butyl ester

1H-NMR (400 MHz),

(ppm, DMSO-d₆): 7.69 (d, J=8.90 Hz, 1H), 6.99 (d, J=2.68 Hz, 1H), 6.89 (dd, J1=8.90 Hz, J2=2.68 Hz, 1H), 3.04 (s, 6H), 1.46 (s, 9H).

Step 3 Preparation of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoic acid hydrochloride

A mixture of tert-butyl 4-(4-methyl-piperazin-1-yl)-2-nitro benzoate (16.4 g, 51 mmol) and 37% HCl (100 mL) in 1,4-dioxane (200 mL) was stirred at room temperature for about 4 hours. The resulting solid was filtered, washed thoroughly with 1,4-dioxane and dried under vacuum at 45° C. The title compound was obtained as pale yellow solid (13.45 g, 87.5% yield) and it was used in the next step without further purification.

1H-NMR (400 MHz),

(ppm. DMSO-d₆): 10.27 (bs, 1H), 7.81 (d, J=8.90 Hz, 1H), 7.40 (d, J=2.69 Hz, 1H), 7.24 (dd, J1=8.90 Hz, J2=2.69 Hz, 1H), 4.13 (bs, 2H), 3.55-3.06 (bs, 6H), 2.83 (s, 3H).

Operating in an analogous way, the following compounds were obtained:

4-morpholin-4-yl-2-nitro-benzoic acid

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.98 (bs, 1H), 7.78 (d, J=8.91 Hz, 1H), 7.30 (d, J=2.44 Hz, 1H), 7.15 (dd, J1=8.91 Hz, J2=2.44 Hz, 1H), 3.73 (m, 4H), 3.33 (m, 4H).

4-dimethylamino-2-nitro-benzoic acid

1H-NMR (400 MHz),

(ppm. DMSO-d₆): 12.81 (bs, 1H), 7.72 (d, J=8.90 Hz, 1H), 6.96 (d, J=2.57 Hz, 1H), 6.84 (dd, J1=8.90 Hz, J2=2.58 Hz, 1H), 3.01 (s, 6H).

Example 2 Preparation of 3-pyrrolidin-1-ylmethyl-benzoyl chloride hydrochloride Step 1 Preparation of 3-pyrrolidin-1-ylmethyl-benzoic acid methyl ester

To a stirred solution of pyrrolidine (7.3 mL, 87 mmol) in dry tetrahydrofuran (5 mL), a solution of 3-bromomethyl-benzoic acid methyl ester (2.0 g, 8.7 mmol) in 5 mL of dry tetrahydrofuran was added dropwise and the mixture stirred at room temperature for 4 hours. The reaction mixture was then poured into 100 mL of saturated aqueous solution of sodium hydrogenocarbonate, extracted with 100 mL of ethyl acetate, dried over sodium sulfate and evaporated to dryness affording the title compound as yellow oil (1.85 g).

1H-NMR (400 MHz),

(ppm, DMSO-d₆): 7.91 (m, 1H), 7.85 (m, 1H), 7.59 (m, 1H), 7.48 (m, 1H), 3.86 (s, 3H), 3.64 (s, 2H), 2.44 (m, 4H), 1.71 (m, 4H).

Step 2

Preparation of 3-pyrrolidin-1-ylmethyl-benzoic acid hydrochloride

A solution of 3-pyrrolidin-1-ylmethyl-benzoic acid methyl ester (800 mg, 3.6 mmol) in aqueous 25% hydrochloric acid (15 mL) was stirred at 90° C. for 4 hours. The solvent was evaporated affording the title compound as brown oil (quantitative) that was used as such for the next step.

Step 3

Preparation of 3-pyrrolidin-1-ylmethyl-benzoyl chloride hydrochloride

A suspension of 3-pyrrolidin-1-ylmethyl-benzoic acid hydrochloride (850 mg, 3.5 mmol) in dry tetrahydrofuran was treated with 2.55 mL of thionyl chloride (35 mmol, 10 eq) and stirred at room temperature for 2 hours. The solution thus obtained was then evaporated to dryness, the residue suspended in dry toluene, evaporated to dryness and dried under vacuum affording the title compound as pale brown solid (quantitative).

Example 3 Preparation of 6,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester [(IV) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R1=nitro, R2=4-methyl-piperazin-1-yl]

4-(4-methylpiperazin-1-yl)-2-nitrobenzoic acid (15 g, 49.7 mmol) in dry tetrahydrofuran (100 mL) was treated with thionyl chloride (5 eq., 18.1 mL, 248.7 mmol) and few drops of N,N-dimethylformamide at 80° C. for 14 hours. After removal of the solvent under vacuum, the crude material was added portion-wise to a solution of 3-amino-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (16.1 g, 49.7 mmol) and diisopropylethylamine (5 eq., 43.4 mL, 248.7 mmol) in 1,4-dioxane (200 mL) maintained under magnetic stirring at 80° C. The reaction mixture was stirred for about 6 hours at 80° C. After removal of the solvent, the crude material was diluted with dichloromethane (200 mL), saturated sodium hydrogenocarbonate (200 mL), dried over sodium sulfate, evaporated to dryness and purified by flash chromatography on silica gel, using acetone as eluant. The title compound was obtained as light yellow powder (13.5 g, 47% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.70, 10.67 (s, 1H), 7.68, 7.66 (d, J1=8.78 Hz, 1H), 7.48 (bs, 1H), 7.30 (dd, J1=8.78 Hz, J2=2.56 Hz, 1H), 4.47-4.39 (m, 4H), 3.41 (m, 4H), 2.52 (m, 4H), 2.27 (s, 3H), 1.63, 1.62 (s, 6H), 1.49, 1.46 (s, 9H), 1.37, 1.36 (t, J=7.07 Hz, 3H), mixture of rotamers.

Operating in an analogous way, and using the suitable carboxylic acid, the following compounds were also obtained:

6,6-dimethyl-3-(2-nitro-benzoylamino)-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester [(IV) Q=ethyl, Ra=Rb=methyl, A=B=D=E=CH, R1=nitro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.97, 10.94 (s, 1H), 8.27, 8.21 (d, J=8.05 Hz, 1H), 7.98-7.76 (m, 3H), 4.55-4.48, 4.46-4.38 (m, 4H), 1.65, 1.63 (s, 6H), 1.50, 1.46 (s, 9H), 1.35, 1.34 (t, 3H), mixture of rotamers.

6,6-Dimethyl-3-(4-morpholin-4-yl-2-nitro-benzoylamino)-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester [(IV) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R1=nitro, R2=4-morpholin-4-yl]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.68 (s, 1H), 7.68, 7.66 (d, J=8.65 Hz, 1H), 7.47 (d, 1H), 7.29 (dd, J=8.65 Hz, J2=2.56 Hz, 1H), 4.45-4.36 (m, 4H), 3.73 (m, 4H), 3.34 (m, 4H), 1.61, 1.59 (s, 6H), 1.47, 1.43 (s, 9H), 1.34, 1.33 (t, J=7.08 Hz, 3H), mixture of rotamers.

3-(4-Dimethylamino-2-nitro-benzoylamino)-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester [(IV) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R1=nitro, R2=4-dimethylamino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.65, 10.62 (bs, 1H), 7.67, 7.66 (d, J1=8.70 Hz, 1H), 7.18 (bs, 1H), 7.01 (dd, J1=8.70 Hz, J2=2.56 Hz, 1H), 4.47-4.41 (m, 4H), 3.07 (s, 6H), 1.63, 1.61 (s, 6H), 1.49, 1.46 (s, 9H), 1.37, 1.36 (t, J=7.07 Hz, 3H), mixture of rotamers.

3-(4-Methoxy-2-nitro-benzoylamino)-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester [(IV) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R1=nitro, R2=methoxy]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.84, 10.81 (2 bs, 1H), 7.80-7.74 (m, 1H), 7.71-7.66 (m, 1H), 7.47-7.43 (m, 1H), 4.46-4.33 (m, 4H), 3.94 (s, 3H), 1.64, 1.63 (2bs, 6H), 1.51-1.44 (m, 9H), 1.38-1.32 (m, 3H).

3-(4-Fluoro-2-nitro-benzoylamino)-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester [(IV) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R1=nitro, R2=fluoro]

ESI (+) MS: m/z 492 (MH⁺).

3-(2-Fluoro-6-nitro-benzoylamino)-6,6-dimethyl-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester [(IV) Q=ethyl, Ra=Rb=methyl, A=B=D=CH, E=CR2, R1=nitro, R2=fluoro]

1H-NMR (400 MHz), 6 ppm, CDCl₃): 11.37 (bs, 1H), 8.15 (s, 1H), 8.0 (t, 1H), 7.65 (t, 1H), 7.53 (t, 1H), 4.69 (m, 2H), 4.50 (q, 2H), 1.85 (s, 6H), 1.50 (s, 9H), 1.47 (t, 3H).

Example 4 Preparation of 6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester dihydrochloride [(V) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R1=nitro, R2=4-methyl-piperazin-1-yl]

A solution of 4N HCl in 1,4-dioxane (4 eq., 18.4 mL, 73.6 mmol) was added to a solution of 6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (10.5 g, 18.4 mmol) in 1,4-dioxane (100 mL) at room temperature. Stirring was continued for about 30 hours. After removal of the solvent, the crude material was treated with diethyl ether (2×100 mL) and evaporated to dryness. The title compound was obtained after crystallization from diethyl ether as yellow solid (10 g, quantitative).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.88 (s, 2H), 9.94 (bs, 1H), 7.75 (d, J1=8.78 Hz, 1H), 7.61 (d, J2=2.56 Hz, 1H), 7.40 (dd, J1=8.78 Hz, J2=2.56 Hz, 1H), 4.50-4.43 (m, 4H), 4.14 (m, 2H), 3.51 (m, 2H), 3.45-3.05 (m, 4H), 2.84 (s, 3H), 1.69 (s, 6H), 1.37 (t, J=7.07 Hz, 3H).

Operating in an analogous way, the following compounds were obtained:

6,6-Dimethyl-3-(2-nitro-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester hydrochloride [(V) Q=ethyl, Ra=Rb=methyl, A=B=D=E=CH, R1=nitro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.16 (s, 1H), 10.02, 9.84 (bs, 1H), 8.28, 8.22 (dd, J1=8.17 Hz, J2=0.85 Hz, 1H), 7.95 (ddd, J1=8.05 Hz, J2=7.43 Hz, J3=0.85 Hz, 1H), 7.85 (ddd, J1=8.17 Hz, J2=8.05 Hz, J3=1.47 Hz, 1H), 7.79 (dd, J1=7.43 Hz, J2=1.47 Hz, 1H), 4.58, 4.44 (q, J=7.08 Hz, 2H), 4.51, 4.31 (s, 2H), 1.70 (s, 6H), 1.41, 1.35 (t, J=7.08 Hz, 3H), mixture of rotamers.

6,6-Dimethyl-3-(4-morpholin-4-yl-2-nitro-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carb oxylic acid ethyl ester hydrochloride [(V) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R1=nitro, R2=morpholin-4-yl]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.56 (s, 1H), 7.68 (d, J1=8.66 Hz, 1H), 7.46 (d, J2=2.44 Hz, 1H), 7.29 (dd, J1=8.66 Hz, J2=2.44 Hz, 1H), 4.40 (q, J=7.07 Hz, 2H), 3.88 (s, 2H), 3.75 (m, 4H), 3.34 (m, 4H), 1.37-1.32 (m, 9H).

3-(4-Dimethylamino-2-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester hydrochloride [(V) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R1=nitro, R2=dimethylamino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.78 (s, 1H), 9.83 (bs, NH2+), 7.67 (d, J1=8.90 Hz, 1H), 7.18 (d, J2=2.56 Hz, 1H), 7.02 (dd, J1=8.90 Hz, J2=2.56 Hz, 1H), 4.50 (m, 2H), 4.47 (q, J=7.08 Hz, 2H), 3.08 (s, 6H), 1.68 (s, 6H), 1.38 (t, J=7.08 Hz, 3H).

3-(4-Methoxy-2-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(V) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R1=nitro, R2=methoxy]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.01 (s, 1H), 9.91 (bs, 2H), 7.79 (d, J=8.5 Hz, 1H), 7.69 (d, J=2.6 Hz, 1H), 7.47 (dd, J1=2.6 Hz, J2=8.5 Hz, 1H), 4.49 (m, 2H), 4.45 (q, J=7.2 Hz, 2H), 3.95 (s, 3H), 1.69 (s, 6H), 1.37 (t, J=7.2 Hz, 3H).

3-(4-Fluoro-2-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester hydrochloride [(V) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R1=nitro, R2=fluoro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.17 (s, 1H), 9.88 (bs, NH2+), 8.19 (dd, J1=8.77 Hz, J2=2.08 Hz, 1H), 7.91-7.83 (m, 2H), 4.50 (bs, 2H), 4.43 (q, J=7.08 Hz, 2H), 1.70 (s, 6H), 1.35 (t, J=7.08 Hz, 3H).

3-(2-Fluoro-6-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester hydrochloride [(V) Q=ethyl, Ra=Rb=methyl, A=B=D=CH, E=CR2, R1=nitro, R2=fluoro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 9.9 (bs, 1H), 8.75 (bs, 2H), 8.09 (d, 1H), 7.85 (m, 2H), 4.21 (q, 2H), 3.05 (m, 2H), 1.85 (s, 6H), 1.42 (t, 3H).

Example 5 Preparation of 5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=nitro, R2=4-methyl-piperazin-1-yl]

3,5-Difluorobenzesulfonyl chloride (1 eq., 3.9 g, 18.4 mmol) was added portion-wise to a stirred solution of 6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester dihydrochloride (10 g, 18.4 mmol) and N,N-diisopropylethylamine (6 eq., 19.3 mL, 110.4 mmol) in dry dichloromethane (100 mL) at room temperature. Stirring was continued for 4 hours. The reaction mixture was diluted with dichloromethane (100 mL) then washed with saturated sodium hydrogenocarbonate (150 mL), dried over sodium sulfate, evaporated to dryness and purified by flash chromatography on silica gel, using acetone as eluant. The title compound was obtained as yellow solid (9 g, 65% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.71 (s, 1H), 7.69-7.62 (m, 4H), 7.47 (d, J2=2.44 Hz, 1H), 7.29 (dd, J1=9.03 Hz, J2=2.44 Hz, 1H), 4.58 (s, 2H), 4.43 (q, J=7.07 Hz, 2H), 3.41 (m, 4H), 2.50 (m, 4H), 2.26 (s, 3H), 1.67 (s, 6H), 1.35 (t, J=7.07 Hz, 3H).

Operating in an analogous way, the following compounds were obtained:

5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-3-(2-nitro-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=nitro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.02 (s, 1H), 8.22 (dd, J1=8.17 Hz, J2=0.86 Hz, 1H), 7.93 (ddd, J1=8.05 Hz, J2=7.44 Hz, J3=0.86 Hz, 1H), 7.83 (ddd, J1=8.17 Hz, J2=8.05 Hz, J3=1.46 Hz, 1H), 7.78 (dd, J1=7.44 Hz, J2=1.46 Hz, 1H), 7.68 (m, 1H), 7.64 (m, 2H), 4.62, 4.59 (s, 2H), 4.51, 4.41 (q, J=7.07 Hz, 2H), 1.70 (s, 6H), 1.37, 1.33 (t, J=7.07 Hz, 3H), mixture of rotamers.

5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-3-(4-morpholin-4-yl-2-nitro-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=nitro, R2=morpholin-4-yl]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.71 (s, 1H), 7.66 (d, J1=8.78 Hz, 1H), 7.67-7.59 (m, 3H), 7.46 (d, J2=2.56 Hz, 1H), 7.28 (dd, J1=8.78 Hz, J2=2.56 Hz, 1H), 4.56 (s, 2H), 4.40 (q, J=7.07 Hz, 2H), 3.73 (m, 4H), 3.35 (m, 4H), 1.65 (s, 6H), 1.32 (t, J=7.07 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-3-(4-dimethylamino-2-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=nitro, R2=dimethylamino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.64 (s, 1H), 7.66-7.59 (m, 4H), 7.16 (d, J2=2.56 Hz, 1H), 6.98 (dd, J1=8.90 Hz, J2=2.56 Hz, 1H), 4.56 (s, 2H), 4.41 (q, J=7.08 Hz, 2H), 3.04 (s, 6H), 1.64 (s, 6H), 1.33 (t, J=7.08 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-3-(4-methoxy-2-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=nitro, R2=methoxy]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.88 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.70-7.62 (m, 4H), 7.46 (dd, J1=2.6 Hz, J2=8.5 Hz, 1H), 4.58 (bs, 2H), 4.42 (q, J=7.1 Hz, 2H), 3.94 (s, 3H), 1.69 (s, 6H), 1.34 (t, J=7.1 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-3-(4-fluoro-2-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=nitro, R2=fluoro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.03 (s, 1H), 8.16 (dd, J1=8.65 Hz, J2=2.44 Hz, 1H), 7.90-7.82 (m, 2H), 7.71-7.62 (m, 3H), 4.58 (s, 2H), 4.41 (q, J=7.07 Hz, 2H), 1.69 (s, 6H), 1.33 (t, J=7.07 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-3-(2-fluoro-6-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl, R1=nitro, R2=fluoro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.03 (s, 1H), 8.11 (d, 1H), 7.80-7.89 (m, 2H), 7.66-7.72 (m, 3H), 4.61 (s, 2H), 4.42 (q, 3H), 1.86 (s, 6H), 1.34 (t, 3H).

Example 6 Preparation of 3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester hydrochloride [(VII) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=amino, R2=4-methyl-piperazin-1-yl]

A suspension of 5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (1.50 g, 2.3 mmol), cyclohexene (15 eq., 20 mL), 2N HCl (13 eq., 15 mL), in THF/water/ethanol (2:1.5:1.5, 50 mL) was treated with 10% Pd—C (0.2 eq., 0.55 g). The reaction mixture was stirred at 70° C. for 3 hours, then filtered, washed thoroughly with THF, followed by ethanol and evaporated to dryness. The title compound was obtained as beige powder (1.4 g, 93% yield) and it was used in the next steps without further purification.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.60, 10.40 (bs, 1H), 7.64 (m, 3H), 7.34 (d, J1=9.02 Hz, 1H), 6.68 (bs, NH3+), 6.39 (dd, J1=9.02 Hz, J2=2.31 Hz, 1H), 6.26 (d, J2=2.31 Hz, 1H), 4.71 (s, 2H), 4.43 (q, J=7.07 Hz, 2H), 3.88 (m, 2H), 3.48 (m, 2H), 3.11 (m, 4H), 2.81, 2.80 (s, 3H), 1.63 (s, 6H), 1.34 (t, J=7.07 Hz, 3H), mixture of rotamers.

Example 7 Preparation of 3-(2-amino-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=amino]

A suspension of 5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-(2-nitro-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (8.0 g, 0.017 mol) cyclohexene (20 mL) in dioxane (200 mL) was heated at 90° C. and 5% Pd/C (1.0 g) was carefully added in small portions. Stiffing was continued for 5 hours at 90° C., then the catalyst was filtered through Celite and the pad washed with warm 1,4-dioxane (100 mL). After evaporation of the solvent, the crude material was suspended in hexane (100 mL), stirred for about 30 minutes and filtered to yield the title compound as beige solid (7.2 g, 95% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.66 (m, 3H), 7.48 (dd, J1=8.05 Hz, J2=1.34 Hz, 1H), 7.29 (ddd, J1=8.54 Hz, J2=6.95 Hz, J3=1.34 Hz, 1H), 6.83 (dd, J1=8.54 Hz, J2=0.85 Hz, 1H), 6.65 (ddd, J1=8.05 Hz, J2=6.95 Hz, J3=0.85 Hz, 1H), 4.75 (s, 2H), 4.46 (q, J=7.08 Hz, 2H), 1.66 (s, 6H), 1.36 (t, J=7.08 Hz, 3H).

Operating in an analogous way, the following compounds were obtained:

3-(2-Amino-4-morpholin-4-yl-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=amino, R2=morpholin-4-yl]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.54 (bs, 1H), 7.65-7.60 (m, 3H), 7.30 (d, J1=9.03 Hz, 1H), 6.34 (dd, J1=9.03 Hz, J2=2.44 Hz, 1H), 6.20 (d, J2=2.44 Hz, 1H), 4.71 (s, 2H), 4.43 (q, J=7.08 Hz, 2H), 3.70 (m, 4H), 3.17 (m, 4H), 1.63 (s, 6H), 1.34 (t, J=7.08 Hz, 3H).

3-(2-Amino-4-dimethylamino-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=amino, R2=dimethylamino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.66 (bs, 1H), 7.65 (m, 2H), 7.29 (d, J1=9.03 Hz, 1H), 7.18 (m, 1H), 6.18 (dd, J1=9.03 Hz, J2=2.57 Hz, 1H), 6.01 (d, J2=2.57 Hz, 1H), 4.73 (s, 2H), 4.46 (q, J=7.08 Hz, 2H), 2.96 (s, 6H), 1.65 (s, 6H), 1.37 (t, J=7.08 Hz, 3H).

3-(2-Amino-4-methoxy-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=amino, R2=methoxy]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.57 (bs, 1H), 7.70-7.62 (m, 3H), 7.41 (d, J=8.9 Hz, 1H), 6.84 (bs, 2H), 6.35 (d, J=2.5 Hz, 1H), 6.28 (dd, J1=2.5 Hz, J2=8.9 Hz, 1H), 4.74 (bs, 2H), 4.46 (q, J=7.1 Hz, 2H), 3.76 (s, 3H), 1.66 (s, 6H), 1.36 (t, J=7.1 Hz, 3H).

3-(2-Amino-4-fluoro-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=amino, R2=fluoro]

ESI (+) MS: m/z 538 (MH⁺).

3-(2-Amino-6-fluoro-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl, R1=amino, R2=fluoro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.24 (s, 1H), 7.65 (m, 3H), 7.12 (m, 1H), 6.58 (d, 1H), 6.34 (m, 1H), 5.92 (s, 2H), 4.70 (s, 2H), 4.42 (q, 2H), 1.83 (s, 6H), 1.34 (t, 3H).

Example 8 Preparation of 1-methyl-1H-pyrrole-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(1-methyl-1H-pyrrole-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 12

1-Methyl-1H-pyrrole-2-carbonyl chloride (3 eq., 0.225 g, 1.57 mmol) was added to the mixture of 3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester hydrochloride (0.34 g, 0.52 mmol) and N,N-diisopropylethylamine (6 eq., 0.54 mL, 3.12 mmol) in dry dichloromethane (10 mL), maintained under stirring at room temperature. After 2 hours, 1-methyl-1H-pyrrole-2-carbonyl chloride (5 eq., 0.4 g) and N,N-diisopropylethylamine (22 eq., 2 mL) were added and stirring was continued for 20 hours. The mixture was diluted with dichloromethane (100 mL), washed with saturated sodium hydrogenocarbonate (100 mL), dried over sodium sulfate and evaporated to dryness. The crude material was then treated with triethylamine (5 mL) and methanol (20 mL) at room temperature for 20 hours. After removal of the solvent, the mixture was purified by flash chromatography on silica gel, using dichloromethane-methanol-30% NH₄OH 100:10:1 as eluant, to yield the title compound (0.145 g, 42% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.56, 12.46 (bs, 1H), 12.26 (bs, 1H), 10.87, 10.83 (bs, 1H), 8.30 (bs, 1H), 7.95, 7.82 (m, bs, 1H), 7.68 (m, 1H), 7.59 (m, 2H), 7.09 (m, 1H), 6.88, 6.84 (m, bs, 1H), 6.76, 6.68 (m, bs, 1H), 6.15 (m, 1H), 4.65, 4.55 (bs, 2H), 3.94 (s, 3H), 3.39-3.28 (m, bs, 4H), 2.47 (m, 4H), 2.25 (s, 3H), 1.71, 1.66 (s, 6H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

1H-Pyrrole-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 10

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.54, 12.44 (s, 1H), 12.24 (s, 1H), 11.73 (s, 1H), 10.85, 10.81 (s, 1H), 8.30 (bs, 1H), 7.93, 7.79 (d, J=8.78 Hz, 1H), 7.66 (m, 1H), 7.58 (m, 2H), 7.03 (m, 1H), 6.79-6.64 (m, 2H), 6.21 (m, 1H), 4.64, 4.54 (s, 2H), 3.36-3.26 (m, 4H), 2.45 (m, 4H), 2.22 (s, 3H), 1.68, 1.64 (s, 6H), mixture of tautomers.

2-Benzoylamino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=benzoylamino, R2=4-methyl-piperazin-1-yl], cpd. 22

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.89, 12.62 (s, 1H), 12.59, 12.33 (s, 1H), 10.98, 10.91 (s, 1H), 8.39 (d, J2=2.44 Hz, 1H), 7.99, 7.85 (m, 3H), 7.68 (m, 2H), 7.59 (m, 4H), 6.85, 6.75 (m, 1H), 4.72, 4.58 (m, 2H), 3.35 (m, 4H), 2.48 (m, 4H), 2.25 (s, 3H), 1.70, 1.65 (s, 6H), mixture of tautomers.

Thiophene-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(thiophene-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 24

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.81, 12.60, 12.57, 12.31 (4 bs, 2H), 10.93, 10.88 (2 bs, 1H), 8.24 (d, J=2.6 Hz, 1H), 8-7.7 (m, 2H), 7.94 (dd, J1=4.9 Hz, J2=1 Hz, 1H), 7.68 (bt, 1H), 7.61 (bd, 2H), 7.26 (dd, J1=3.8 Hz, J2=4.9 Hz, 1H), 6.83, 6.74 (2bd, 1H), 4.69, 4.56 (2bs, 2H), 3.35 (m, 4H), 2.48 (bt, 4H), 2.25 (s, 4H), 1.70, 1.66 (2bs, 6H), mixture of tautomers.

5-Methyl-2H-pyrazole-3-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide trifluoroacetate [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(5-methyl-2H-pyrazole-3-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 31

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 13.11 (bs, 1H), 12.22 (bs, 1H), 10.87 (bs, 1H), 9.75 (bs, 1H), 8.40 (d, J=2.4 Hz, 1H), 7.86 (d, J=8.9 Hz, 1H), 7.7-7.6 (m, 3H), 6.83 (dd, J1=9.3 Hz, J2=2.1 Hz), 6.50 (s, 1H), 4.60 (s, 1H), 4.02 (2bs, 2H), 3.57 (2bs, 2H), 3.25-3.05 (m, 4H), 2.89 (s, 3H), 2.31 (s, 3H), 1.67 (s, 6H).

Thiazole-4-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(thiazole-4-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 34

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.8-12.2 (4bs, 2H), 10.84, 10.79 (2bs, 1H), 9.21 (bs, 1H), 8.50 (d, J=1.8 Hz, 1H), 8.42, 8.39 (2bs, 1H), 7.9-7.75 (2bd, 1H), 7.66 (bt, 1H), 7.61 (bd, 2H), 6.84-6.74 (2bd, 1H), 4.66, 4.54 (2bs, 2H), 3.34 (m, 4H), 2.49 (m, 4H), 2.26 (s, 3H), 1.70, 1.65 (2bs, 6H), mixture of tautomers.

3-Methyl-thiophene-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(3-methyl-thiophene-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 35

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.56, 12.31 (2bs, 1H), 12.14, 12.09 (2bs, 1H), 10.92, 10.85 (2bs, 1H), 8.27 (d, J=2.4 Hz, 1H), 7.95 (bd, 1H), 7.73 (d, J=5 Hz, 1H), 7.69 (bt, 1H), 7.6-7.55 (m, 2H), 7.09 (d, J=5 Hz, 1H), 6.73 (d, 1H), 4.61, 4.53 (2bs, 2H), 3.3 (m, 4H), 2.57 (bs, 3H), 2.48 (m, 4H), 2.25 (s, 3H), 1.70, 1.65 (2bs, 6H), mixture of tautomers.

2-[(3-Pyrrolidin-1-ylmethyl-benzoyl)amino]-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=(3-pyrrolidin-1-ylmethyl-benzoyl)amino], cpd. 67

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.54 (bs, 1H), 11.84 (bs, 1H), 11.22 (bs, 1H), 8.50 (d, J=8.05 Hz, 1H), 7.94 (d, J=7.43 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J=7.68 Hz, 1H), 7.68-7.48 (m, 6H), 7.24 (m, 1H), 4.65 (bs, 2H), 3.67 (s, 2H), 2.45 (m, bs, 4H), 1.70-1.61 (m, bs, 10H).

Tetrahydro-furan-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(tetrahydro-furan-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 144

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.51, 12.04 (s, 1H), 12.15, 11.99 (s, 1H), 10.78, 10.76 (s, 1H), 8.23 (m, bs, 1H), 7.86, 7.73 (d, J1=9.02 Hz, 1H), 7.65 (m, 1H), 7.53 (m, 2H), 6.77, 6.67 (d, bs, J1=9.02 Hz, 1H), 4.60, 4.53 (m, bs, 2H), 4.36 (dd, J1=8.66 Hz, J2=5.00 Hz, 1H), 4.02 (m, 1H), 3.86 (m, 1H), 3.30-3.24 (m, 4H), 2.44 (m, bs, 4H), 2.29-2.20 (m, 4H), 2.00-1.78 (m, 3H), 1.68, 1.64 (s, 6H), mixture of tautomers.

(S)-Tetrahydro-furan-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=((S)-tetrahydro-furan-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 1

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.51, 12.04 (s, 1H), 12.15, 11.99 (s, 1H), 10.78, 10.76 (s, 1H), 8.23 (m, bs, 1H), 7.86, 7.73 (d, J1=9.02 Hz, 1H), 7.65 (m, 1H), 7.53 (m, 2H), 6.77, 6.67 (d, bs, J1=9.02 Hz, 1H), 4.60, 4.53 (m, bs, 2H), 4.36 (dd, J1=8.66 Hz, J2=5.00 Hz, 1H), 4.02 (m, 1H), 3.86 (m, 1H), 3.30-3.24 (m, 4H), 2.44 (m, bs, 4H), 2.29-2.20 (m, 4H), 2.00-1.78 (m, 3H), 1.68, 1.64 (s, 6H), mixture of tautomers.

(R)-Tetrahydro-furan-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=((R)-tetrahydro-furan-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 2

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.51, 12.04 (s, 1H), 12.15, 11.99 (s, 1H), 10.78, 10.76 (s, 1H), 8.23 (m, bs, 1H), 7.86, 7.73 (d, J1=9.02 Hz, 1H), 7.65 (m, 1H), 7.53 (m, 2H), 6.77, 6.67 (d, bs, J1=9.02 Hz, 1H), 4.60, 4.53 (m, bs, 2H), 4.36 (dd, J1=8.66 Hz, J2=5.00 Hz, 1H), 4.02 (m, 1H), 3.86 (m, 1H), 3.30-3.24 (m, 4H), 2.44 (m, bs, 4H), 2.29-2.20 (m, 4H), 2.00-1.78 (m, 3H), 1.68, 1.64 (s, 6H), mixture of tautomers.

Tetrahydro-furan-3-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(tetrahydro-furan-3-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 6

1H-NMR (500 MHz), δ (ppm, DMSO-d₆): 12.47, 12.13 (2bs, 1H), 11.56, 11.35 (2bs, 1H), 10.74, 10.72 (2s, 1H), 8.00 (bs, 1H), 7.80, 7.69 (2d, 1H), 7.61 (m, 1H), 7.56 (m, 2H), 6.73, 6.63 (2d, 1H), 4.55, 4.47 (2bs, 2H), 3.90-3.62 (m, 4H), 3.23 (m, 4H), 3.13 (m, 1H), 2.40 (m, 4H), 2.18 (s, 3H), 2.11 (m, 1H), 2.05 (m, 1H), 1.64, 1.59 (2s, 6H), mixture of tautomers.

(S)-1-Methyl-pyrrolidine-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=((S)-1-methyl-pyrrolidine-2-carbonyl)amino], cpd. 55

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.61, 12.20 (s, 1H), 11.69, 11.58 (s, 1H), 11.14, 11.12 (s, 1H), 8.50 (d, J=8.24 Hz, 1H), 7.85, 7.78 (d, J=7.94 Hz, 1H), 7.72-7.51 (m, 4H), 7.24, 7.15 (m, 1H), 4.65, 4.56 (s, 2H), 3.39-3.29 (m, 1H), 3.09 (m, 1H), 2.94 (m, 1H), 2.44-2.34 (m, 4H), 2.21 (m, 1H), 1.82-1.65 (m, 8H), mixture of tautomers.

(S)-1-Methyl-pyrrolidine-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide {(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=[(S)-1-methyl-pyrrolidine-2-carbonyl]amino, R2=methoxy}, cpd. 56

-   -   1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.56 (bs, 1H), 12.2-12.0         (m, 2H), 10.93 (bs, 1H), 8.26 (m, 1H), 8.0-7.75 (m, 1H), 7.69         (m, 1H), 7.54 (m, 2H), 6.9-6.65 (m, 1H), 4.64, 4.56 (2bs, 2H),         3.82 (bs, 1H), 3.11 (m, 1H), 2.95 (m, 1H), 2.45-2.30 (m, 4H),         2.21 (m, 1H), 1.85-1.55 (m, 8H), mixture of tautomers.

Tetrahydro-pyran-4-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(tetrahydro-pyran-4-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 7

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.52, 12.22 (s, 1H), 11.68, 11.47 (s, 1H), 10.80, 10.76 (bs, 1H), 8.13 (s, 1H), 7.85, 7.73 (d, J=8.85 Hz, 1H), 7.76 (m, 1H), 7.58 (m, 2H), 6.76, 6.66 (d, bs, J=8.85 Hz, 1H), 4.59, 4.50 (s, 2H), 3.91 (m, 2H), 3.42-3.26 (m, 6H), 2.56 (m, 1H), 2.44 (m, bs, 4H), 2.22 (s, 3H), 1.82 (m, bs, 2H), 1.67-1.63 (m, 8H), mixture of tautomers.

Tetrahydro-pyran-4-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(tetrahydro-pyran-4-carbonyl)amino, R2=dimethylamino], cpd. 69

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.50, 12.19 (s, 1H), 11.87, 11.64 (s, 1H), 10.70, 10.67 (s, 1H), 7.97 (bs, 1H), 7.86, 7.73 (d, J=9.14 Hz, 1H), 7.65 (m, 1H), 7.58 (m, 2H), 6.50, 6.41 (m, bs, 1H), 4.59, 4.50 (s, 2H), 3.91 (m, 2H), 3.40 (m, 2H), 3.00, 2.99 (s, 6H), 2.57 (m, 1H), 1.83 (m, 2H), 1.71-1.60 (m, 8H), mixture of tautomers.

Tetrahydro-pyran-4-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, 121=(Tetrahydro-pyran-4-carbonyl)amino, R2=morpholin-4-yl], cpd. 70

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.54, 12.24, 11.68, 11.46 10.83, 10.80 (6bs, 3H), 8.15 (bd, J=2.3 Hz, 1H), 7.90, 7.88, 7.78, 7.76 (2bd, 1H), 7.67 (bt, 1H), 7.60 (bd, 2H), 6.85-6.65 (m, 1H), 4.61, 4.52 (2bs, 2H), 3.92 (m, 2H), 3.75 (m, 4H), 3.41 (m, 2H), 3.26 (m, 4H), 2.58 (m, 1H), 1.9-1.6 (m, 10H), mixture of tautomers.

5-Methyl-isoxazole-4-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(5-methyl-isoxazole-4-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 23

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.36, 12.13 (bs, 1H), 10.63, 10.56 (bs, 1H), 9.58 (bs, 1H), 8.25 (bs, 1H), 7.63 (m, 3H), 7.39 (d, J=8.78 Hz, 1H), 6.60 (m, bs, 1H), 4.71, 4.57 (bs, 2H), 3.91-3.01 (m, bs, 8H), 2.85 (s, 3H), 1.96 (s, 3H), 1.64 (bs, 6H), mixture of tautomers.

1H-Pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-fluoro-phenyl}-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino, R2=fluoro], cpd. 39

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.63, 12.39 (s, 1H), 12.06 (s, 1H), 11.92, 11.81 (s, 1H), 11.26, 11.20 (s, 1H), 8.43, 8.40 (d, J2=2.68 Hz, 1H), 8.08, 7.97 (m, 1H), 7.67 (m, 1H), 7.58 (m, 2H), 7.09, 6.99 (m, 1H), 7.06 (m, 1H), 6.82, 6.75 (m, 1H), 6.23 (m, 1H), 4.66, 4.54 (s, 2H), 1.69-1.64 (s, 6H), mixture of tautomers.

1H-Pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino, R2=methoxy], cpd. 40

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.62, 12.34, 12.30, 12.06, 11.87, 11.07, 11.03 (7bs, 4H), 8.32 (m, 1H), 8.1-7.9 (m, 1H), 7.69 (bt, 1H), 7.60 (bd, 2H), 7.06 (m, 1H), 6.85-6.65 (m, 2H), 6.25 (m, 1H), 4.68, 4.67 (2bs, 2H), 3.86 (bs, 3H), 1.72, 1.67 (2bs, 6H), mixture of tautomers.

1-Methyl-1H-pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(1-methyl-1H-pyrrole-2-carbonyl)amino, R2=morpholin-4-yl], cpd. 59

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.57, 12.46, 12.25 (3bs, 2H), 10.90, 10.84 (2bs, 1H), 8.32 (m, 1H), 8.0-7.80 (m, 1H), 7.68 (m, 1H), 7.59 (m, 2H), 7.09 (m, 1H), 6.90-6.65 (m, 2H), 6.16 (m, 1H), 4.66, 4.56 (2bs, 2H), 3.94 (bs, 3H), 3.78 (m, 4H), 3.35-3.25 (m, 4H), 1.71, 1.66 (2bs, 6H), mixture of tautomers.

1H-Pyrrole-2-carboxylic acid [2-(5-benzenesulfonyl-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl)-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=phenyl, R1=(1H-pyrrole-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 102

1H-NMR (600 MHz), δ (ppm, DMSO-d₆): 12.49, 12.44, 12.21, 12.16 (4s, 2H), 11.73 (s, 1H), 10.81, 10.77 (2s, 1H), 8.27 (m, 1H), 7.93-7.73 (m, 3H), 7.65 (m, 1H), 7.58 (m, 2H), 7.02 (m, 1H), 6.77-6.61 (m, 2H), 6.23 (m, 1H), 4.53, 4.42 (2s, 2H), 3.3 (m, 4H), 2.44 (m, 4H), 2.21 (bs, 3H), 1.67, 1.61 (2s, 6H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-dimethylamino-acetylamino)-benzamide [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=2-dimethylamino-acetylamino], cpd. 145

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.61, 12.24 (2bs, 1H), 11.57 (bs, 1H), 11.14 (bs, 1H), 8.49 (m, 1H), 7.84 (m, 1H), 7.68 (m, 1H), 7.59-7.51 (m, 3H), 7.16 (m, 1H), 4.66, 4.58 (2bs, 2H), 3.08 (s, 2H), 2.30 (s, 6H), 1.73, 1.67 (2bs, 6H), mixture of tautomers.

Example 9 Preparation of 5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-{2-[(1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino]

A solution of 1H-pyrrole-2-carboxylic acid (0.8 g, 7.2 mmol) in dry dichloromethane (10 mL), oxalyl chloride (5.8 mL, 68.5 mmol) and two drops of N,N-dimethylformamide was stiffed at room temperature overnight. The solvent was evaporated under reduced pressure, the residue dissolved in dry dichloromethane (10 mL) and added to a solution of 3-(2-amino-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (2.5 g, 4.8 mmol), N,N-diisopropylethylamine (4 eq., 3.3 mL, 19.6 mmol) in dry dichloromethane (60 mL). The reaction mixture was stirred at room temperature overnight, washed with 1N HCl (50 mL), saturated sodium hydrogenocarbonate (50 mL), brine (50 mL) and dried over sodium sulfate. The solvent was removed under vacuum and the crude residue purified by flash chromatography on silica gel, using hexane-ethyl acetate 6:4 as eluant, yielding the title compound as colourless solid (2.6 g, 88% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.84 (s, 1H), 11.09 (s, 1H), 10.89 (s, 1H), 8.32 (d, J=8.24 Hz, 1H), 7.81 (d, bs, J=7.94 Hz, 1H), 7.70-7.59 (m, 4H), 7.29 (m, 1H), 7.02 (m, 1H), 6.84 (m, 1H), 6.22 (m, 1H), 4.71 (s, 2H), 4.38 (q, J=7.02 Hz, 2H), 1.68 (s, 6H), 1.31 (t, J=7.02 Hz, 3H).

Operating in an analogous way, the following compounds were obtained:

5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-3-{2-[(1-methyl-1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=(1-methyl-1H-pyrrole-2-carbonyl)amino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.09 (s, 1H), 10.88 (s, 1H), 8.32 (d, bs, J=8.05 Hz, 1H), 7.83 (dd, J1=8.05 Hz, J2=1.34 Hz, 1H), 7.72-7.59 (m, 4H), 7.31 (ddd, bs, J1=8.29 Hz, J2=7.50 Hz, 1H), 7.09 (m, 1H), 6.89 (dd, J1=4.02 Hz, J2=1.70 Hz, 1H), 6.15 (dd, J1=4.02 Hz, J2=2.56 Hz, 1H), 4.71 (s, 2H), 4.40 (q, J=7.07 Hz, 2H), 3.88 (s, 3H), 1.70 (s, 6H), 1.33 (t, J=7.07 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-3-{4-morpholin-4-yl-2-[(1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino, R2=morpholin-4-yl]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.88 (s, 1H), 11.77 (s, 1H), 10.75 (s, 1H), 8.22 (d, J2=2.57 Hz, 1H), 7.67 (m, 1H), 7.65 (d, J1=9.02 Hz, 1H), 7.61 (m, 2H), 7.04 (m, 1H), 6.83 (dd, J1=9.02 Hz, J2=2.57 Hz, 1H), 6.77 (m, 1H), 6.23 (m, 1H), 4.72 (s, 2H), 4.41 (q, J=7.08 Hz, 2H), 3.75 (m, 4H), 3.33-3.24 (m, 4H), 1.68 (s, 6H), 1.33 (t, J=7.08 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-3-{4-dimethylamino-2-[(1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino, R2=dimethylamino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.09 (bs, 1H), 11.82 (bs, 1H), 10.73 (s, 1H), 8.10 (d, J2=2.57 Hz, 1H), 7.70 (m, 1H), 7.65-7.62 (m, 3H), 7.06 (m, 1H), 6.78 (m, 1H), 6.59 (dd, J1=9.15 Hz, J2=2.57 Hz, 1H), 6.25 (m, 1H), 4.74 (s, 2H), 4.44 (q, J=7.07 Hz, 2H), 3.06 (s, 6H), 1.70 (s, 6H), 1.36 (t, J=7.07 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-3-{2-fluoro-6-[(1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester [(VII) Q=ethyl, Ra=Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino, R2=fluoro]

1H-NMR (400 MHz), δ (ppm, CDCl₃): 11.97 (s, 1H), 9.34 (s, 1H), 9.08 (d, 1H), 8.64 (d, 1H), 7.50 (m, 3H), 7.03 (m, 2H), 6.88 (m, 2H), 6.42 (s, 1H), 4.79 (s, 2H), 4.52 (q, 2H), 1.97 (s, 6H), 1.47 (t, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-3-(2-{[1-(toluene-4-sulfonyl)-1H-pyrrole-3-carbonyl]-amino}-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester {(VII) Q=ethyl, Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=[1-(toluene-4-sulfonyl)-1H-pyrrole-3-carbonyl]-amino}

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.81 (s, 1H), 10.74 (s, 1H), 8.02 (dd, J1=2.20 Hz, J2=1.70 Hz, 1H), 7.96 (m, 3H), 7.81 (dd, J1=7.80 Hz, J2=1.46 Hz, 1H), 7.70-7.59 (m, 4H), 7.51-7.46 (m, 3H), 7.36 (m, 1H), 6.74 (dd, J1=3.29 Hz, J2=1.70 Hz, 1H), 4.69 (bs, 2H), 4.31 (q, J=7.07 Hz, 2H), 2.41 (s, 3H), 1.68 (s, 6H), 1.26 (t, J=7.07 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-3-(4-dimethylamino-2-{[1-(toluene-4-sulfonyl)-1H-pyrrole-3-carbonyl]-amino}-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester {(VII) Q=ethyl, Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=[1-(toluene-4-sulfonyl)-1H-pyrrole-3-carbonyl]-amino, R2=dimethylamino}

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.77 (s, 1H), 10.73 (s, 1H), 7.96 (d, J=8.42 Hz, 1H), 7.89 (m, 1H), 7.86 (d, J2=2.56 Hz, 1H), 7.65-7.61 (m, 3H), 7.49-7.47 (m, 1H), 7.47 (d, J=8.42 Hz, 2H), 6.70 (m, 1H), 6.59 (dd, J1=9.02 Hz, J2=2.56 Hz, 1H), 4.73 (s, 2H), 4.38 (q, J=7.08 Hz, 1H), 3.02 (s, 6H), 2.38 (s, 3H), 1.66 (s, 6H), 1.30 (t, J=7.08 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-3-{2-[(pyridine-2-carbonyl)-amino]-benzoylamino}-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester [(VII) Q=Ethyl, Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=(pyridine-2-carbonyl)-amino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.7 (bs, 1H), 10.9 (bs, 1H), 8.69 (m, 2H), 8.20 (d, 1H), 8.11 (t, 1H), 7.89 (d, J=7.94 Hz, 1H), 7.70-7.59 (m, 4H), 7.24 (t, 1H), 4.75 (s, 2H), 4.38 (q, J=7.02 Hz, 2H), 1.68 (s, 6H), 1.31 (t, J=7.02 Hz, 3H).

Example 10 Preparation of 1H-pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino], cpd. 36

A solution of 5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-{2-[(1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (1.2 g, 1.9 mmol) and triethylamine (3 eq., 0.82 mL, 5.9 mmol) in dichloromethane-MeOH 1:1 (40 mL) was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography, using ethyl acetate-hexane 6:4 as eluant, to yield the title compound as colourless solid (0.92 g, 90% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.62, 12.38 (bs, 1H), 11.85 (bs, 1H), 11.70, 11.45 (bs, 1H), 11.21 (s, 1H), 8.53 (d, J=8.29 Hz, 1H), 7.95, 7.88 (m, bs, 1H), 7.67 (m, 1H), 7.58 (m, 3H), 7.24-7.15 (m, bs, 1H), 7.02 (m, 2H), 6.82, 6.76 (m, bs, 1H), 6.22 (m, 1H), 4.67, 4.55 (bs, 2H), 1.7 (bs, 6H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=amino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.47, 12.11 (s, 1H), 10.56 (s, 1H), 7.61 (m, 3H), 7.2 (bs, 1H), 6.77 (bs, 1H), 6.59-6.43 (bs, 2H), 4.62, 4.55 (bs, 2H), 1.67, 1.64 (bs, 6H), mixture of tautomers.

2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-morpholin-4-yl-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=amino, R2=morpholin-4-yl]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.35, 11.96 (bs, 1H), 10.24 (s, 1H), 7.65-7.55 (m, 4H), 6.54 (bs, 2H), 6.22 (m, bs, 1H), 6.16 (d, J=1.83 Hz, 1H), 4.53 (bs, 2H), 3.70 (m, 4H), 3.13 (m, 4H), 1.62 (s, 6H), mixture of tautomers.

2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=amino, R2=4-methyl-piperazin-1-yl]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.37, 11.99 (bs, 1H), 10.25 (bs, 1H), 7.67-7.59 (m, 4H), 6.55 (bs, 2H), 6.30-6.15 (m, bs, 2H), 4.56 (bs, 2H), 3.20 (m, bs, 4H), 2.43 (m, 4H), 2.23 (s, 3H), 1.65 (bs, 6H), mixture of tautomers.

2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-methoxy-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=amino, R2=methoxy]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.41, 12.03 (2s, 1H), 10.40, 10.37 (2s, 1H), 7.72-7.57 (m, 4H), 6.73, 6.67 (2bs, 2H), 6.34-6.09 (m, 2H), 4.61, 4.53 (2bs, 2H), 3.75, 3.73 (2s, 3H), 1.67, 1.63 (2s, 6H), mixture of tautomers.

2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-dimethylamino-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=amino, R2=dimethylamino]

ESI (+) MS: m/z 491 (MH⁺).

2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-6-fluoro-benzamide [(I) Ra=Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl, R1=amino, R2=fluoro]

ESI (+) MS: m/z 466 (MH⁺).

1-Methyl-1H-pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=(1-methyl-1H-pyrrole-2-carbonyl)amino], cpd. 58

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.64, 12.38 (s, 1H), 11.68, 11.44 (s, 1H), 11.22 (bs, 1H), 8.52, 8.47 (d, J=8.41 Hz, 1H), 7.96, 7.82 (d, bs, J=8.17 Hz, 1H), 7.71-7.53 (m, 4H), 7.24, 7.16 (m, 1H), 7.09 (bs, 1H), 6.88, 6.83 (m, bs, 1H), 6.26, 6.16 (dd, J1=3.65 Hz, J2=2.43 Hz, 1H), 4.67, 4.54 (s, 2H), 3.98, 3.92 (s, 3H), 1.71, 1.66 (s, 6H), mixture of tautomers.

1H-Pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino, R2=morpholin-4-yl], cpd. 38

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.57, 12.46 (2s, 1H), 12.28, 12.25 (2s, 1H), 11.76 (s, 1H), 10.90, 10.86 (2s, 1H), 8.33 (m, 1H), 7.98, 7.84 (2m, 1H), 7.69 (m, 1H), 7.61 (m, 2H), 7.05 (m, 1H), 6.86-6.66 (m, 2H), 6.24 (m, 1H), 4.67, 4.57 (2s, 2H), 3.77 (m, 4H), 3.30 (m, 4H), 1.71, 1.66 (2s, 6H), mixture of tautomers.

1H-Pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino, R2=dimethylamino], cpd. 37

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.59, 12.37 (bs, 1H), 12.51, 12.20 (bs, 1H), 11.75 (s, 1H), 10.74 (s, 1H), 8.13 (d, J2=2.44 Hz, 1H), 7.92, 7.80 (m, bs, 1H), 7.66 (m, 1H), 7.57 (m, 2H), 7.02 (m, 1H), 6.78, 6.73 (m, bs, 1H), 6.49, 6.43 (m, bs, 1H), 6.21 (m, 1H), 4.64, 4.55 (bs, 2H), 3.01 (s, 6H), 1.68, 1.65 (bs, 6H), mixture of tautomers.

1H-Pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-3-fluoro-phenyl}-amide [(I) Ra=Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino, R2=fluoro], cpd. 123

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.58 (s, 1H), 11.84 (s, 1H), 11.13 (s, 1H), 10.19 (s, 1H), 7.96 (m, 1H), 7.68 (m, 1H), 7.57 (m, 3H), 7.10 (m, 1H), 7.02 (m, 1H), 6.79 (m, 1H), 6.20 (m, 1H), 4.65 (bs, 2H), 1.70 (bs, 6H).

Pyridine-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=(pyridine-2-carbonyl)amino], cpd. 75

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.62, 12.47 (s, 1H), 12.59, 12.39 (s, 1H), 11.23 (s, 1H), 8.72-8.67 (m, 2H), 8.21 (ddd, J1=7.68 Hz, J2=2.07 Hz, J3=0.98 Hz, 1H), 8.10 (ddd, J1=8.53 Hz, J2=7.68 Hz, J3=1.59 Hz, 1H), 7.90, 7.86 (m, bs, 1H), 7.73-7.57 (m, 5H), 7.32, 7.24 (m, bs, 1H), 4.75, 4.59 (s, 2H), 1.72, 1.67 (s, 6H), mixture of tautomers.

Example 11 Preparation of 1H-pyrrole-3-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=(1H-pyrrole-3-carbonyl)amino], cpd. 46

A solution of 5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-(2-{[1-(toluene-4-sulfonyl)-1H-pyrrole-3-carbonyl]-amino}-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (1.1 g, 1.4 mmol) in 1,4-dioxane (30 mL), was treated with 1N NaOH (9 mL) at 60° C. for 8 hours. The reaction mixture was diluted with dichloromethane (50 mL) and then washed with 1N HCl (20 mL), saturated sodium hydrogenocarbonate (20 mL), brine (20 mL), dried over sodium sulfate and evaporated to dryness. The crude material was purified by flash chromatography on silica gel, using dichloromethane-MeOH 95:5 as eluant, to yield the title compound as pale yellow solid (0.6 g, 77% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.61, 12.39 (s, 1H), 11.50 (s, 1H), 11.45 (s, 1H), 11.29, 11.18 (s, 1H), 8.57 (d, J1=8.24 Hz, 1H), 7.92, 7.86 (m, bs, 1H), 7.67-7.52 (m, 4H), 7.42 (m, bs, 1H), 7.20, 7.12 (m, bs, 1H), 6.87 (m, bs, 1H), 6.49 (m, bs, 1H), 4.67, 4.54 (s, 2H), 1.69, 1.64 (s, 6H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

1H-Pyrrole-3-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(1H-pyrrole-3-carbonyl)amino, R2=dimethylamino], cpd. 47

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.40 (bs, 1H), 12.28 (bs, 1H), 11.41 (s, 1H), 10.67 (bs, 1H), 8.18 (d, J2=2.68 Hz, 1H), 7.84 (m, bs, 1H), 7.64 (m, 1H), 7.58 (m, 2H), 7.37 (m, 1H), 6.86 (m, 1H), 6.50 (m, 1H), 6.41 (d, bs, J1=8.90 Hz, 1H), 4.60 (s, 2H), 3.00 (s, 6H), 1.66 (s, 6H).

Example 12 Preparation of 1H-pyrrole-3-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(1H-pyrrole-3-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 11

1-(Toluene-4-sulfonyl)-1H-pyrrole-3-carbonyl chloride (2.4 eq., 2 mmol) was added to the mixture of 2-amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide (0.45 g, 0.82 mmol) and N,N-diisopropylethylamine (6 eq., 0.86 mL, 4.92 mmol) in dry dichloromethane (15 mL), maintained under stirring at room temperature. After 24 hours, methanol (100 mL) was added and stirring was continued for 70 hours. The mixture was then evaporated to dryness, dissolved with 1,4-dioxane (30 mL), treated with 1N NaOH (10 mL) and water (20 mL) stirred at room temperature for 20 hours and diluted with dichloromethane-water 1:1 (200 mL). The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated to dryness. The title compound was obtained after purification on silica gel, using dichloromethane-methanol-30% NH₄OH 100:10:1 as eluant, as beige solid (0.150 g, 29% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.53, 12.24 (s, 1H), 12.21, 12.05 (s, 1H), 11.42 (s, 1H), 10.80, 10.77 (s, 1H), 8.38, 8.37 (bs, 1H), 7.90, 7.77 (d, J1=9.15 Hz, 1H), 7.64 (m, 1H), 7.58 (m, 2H), 7.37 (m, 1H), 6.86 (m, 1H), 6.72, 6.63 (d, bs, J1=9.15 Hz, 1H), 6.51, 6.48 (m, bs, 1H), 4.65, 4.54 (s, 2H), 3.39-3.23 (m, 4H), 2.44 (m, 4H), 2.22 (s, 3H), 1.68, 1.63 (s, 6H), mixture of tautomers.

Example 13 Preparation of 3H-imidazole-4-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(3H-imidazole-4-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 14

Oxalyl chloride (4.15 eq., 0.186 mL, 2.2 mmol) was added to the solution of 1-trityl-1H-imidazole-4-carboxylic acid (4 eq., 0.76 g, 2.14 mmol), N,N-diisopropylethylamine (17 eq., 1.3 mL, 8.8 mmol) and 4-(N,N-dimethylamino)pyridine (4.15 eq., 0.27 g, 2.2 mmol) in dry dichloromethane (10 mL), maintained under stirring at room temperature. After about 10 minutes 3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester hydrochloride (0.35 g, 0.53 mmol) was added and stirring was continued for 6 hours. The mixture was diluted with dichloromethane (100 mL), washed with saturated sodium hydrogenocarbonate (100 mL), dried over sodium sulfate and evaporated to dryness. The resulting dark brown oil was treated with 4N HCl in 1,4-dioxane (10 mL) at room temperature for 20 hours, evaporated, added with triethylamine (5 mL) and methanol (15 mL) and stirred for about 4 hours. After removal of the solvents, the crude material was purified by flash chromatography on silica gel, using dichloromethane-methanol-30% NH₄OH 100:10:1 as eluant, to give the title compound as colourless solid (0.09 g, 26% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.61 (s, 1H), 12.48 (s, 1H), 12.20 (s, 1H), 10.73 (s, 1H), 8.38 (m, bs, 1H), 7.79-7.72 (m, 3H), 7.76-7.56 (m, 3H), 6.70 (m, bs, 1H), 4.62, 4.52 (bs, 2H), 3.31-3.24 (m, 4H), 2.45 (m, 4H), 2.22 (s, 3H), 1.67-1.64 (bs, 6H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

1H-Imidazole-4-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=(1H-imidazole-4-carbonyl)amino], cpd. 57

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.67, 12.38 (s, 1H), 12.58 (s, 1H), 11.62, 11.59 (s, 1H), 11.14 (s, 1H), 8.65, 8.60 (d, J=8.38 Hz, 1H), 7.82-7.52 (m, 7H), 7.22, 7.14 (m, 1H), 4.67, 4.53 (s, 2H), 1.69, 1.64 (s, 6H), mixture of tautomers.

Example 14 Preparation of piperidine-3-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(piperidine-3-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 4

A solution of N-FMOC-piperidine-3-carbonyl chloride (5 eq., 0.85 g, 2.3 mmol) in dry dichloromethane (5 mL) was added to the solution of 3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester hydrochloride (0.30 g, 0.46 mmol) and N,N-diisopropylethylamine (10 eq., 0.80 mL, 4.6 mmol) in dry dichloromethane (10 mL), maintained under stiffing at room temperature. After 20 hours, piperidine (5 mL) and methanol (20 mL) were added to the reaction mixture and stirring was continued for 70 hours at room temperature. After evaporation of the solvent, the crude material was purified by flash chromatography on silica gel, using dichloromethane-methanol-30% NH₄OH 100:10:1 as eluant, to yield the title compound as yellow solid (0.126 g, 41% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.41 (bs, 1H), 11.59 (bs, 1H), 10.78 (bs, 1H), 8.10 (d, J2=2.56 Hz, 1H), 7.79, 7.70 (d, bs, J1=8.78 Hz, 1H), 7.64 (m, 1H), 7.57 (m, 2H), 6.68 (m, bs, 1H), 4.59, 4.55 (bs, 2H), 3.27-3.22 (m, 4H), 3.18 (m, 1H), 3.09 (m, 1H), 2.86 (m, 1H), 2.66 (m, 1H), 2.55-2.46 (m, 1H), 2.42 (m, 4H), 2.21 (s, 3H), 1.95 (m, 2H), 1.68-1.56 (m, 8H), 1.43 (m, 2H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

Piperidine-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(piperidine-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 3

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.48, 12.36 (bs, 1H), 12.10, 11.89 (bs, 1H), 10.72 (bs, 1H), 8.21 (d, J2=2.19 Hz, 1H), 7.76 (m, bs, 1H), 7.65 (m, 1H), 7.54 (m, 2H), 6.84, 6.69 (m, bs, 1H), 4.65, 4.41 (bs, 2H), 3.25 (m, 4H), 3.17 (m, 1H), 2.91 (m, 1H), 2.57 (m, 1H), 2.43 (m, 4H), 2.21 (m, 3H), 1.81 (m, 1H), 1.66 (m, bs, 7H), 1.50-1.29 (m, 4H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-methylamino-acetylamino)-benzamide [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=2-methylamino-acetylamino], cpd. 146

ESI (+) MS: m/z 519 (MH⁺).

(S)-Pyrrolidine-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=(S)-(pyrrolidine-2-carbonyl)amino], cpd. 147

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.56, 12.23 (2bs, 1H), 11.67 (bs, 1H), 11.06 (bs, 1H), 8.46 (m, 1H), 7.79-7.44 (m, 5H), 7.12 (m, 1H), 4.71-4.46 (m, 2H), 3.73 (m, 1H), 2.94 (m, 1H), 2.81 (m, 1H), 2.06 (m, 1H), 1.76 (m, 1H), 1.72-1.58 (m, 8H), mixture of tautomers.

(S)-Pyrrolidine-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(S)-(pyrrolidine-2-carbonyl)amino, R2=methoxy], cpd. 148

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.54, 12.12 (2bs, 2H), 10.90 (bs, 1H), 8.24 (m, 1H), 7.83 (m, 1H), 7.68 (m, 1H), 7.58 (m, 2H), 6.84-6.65 (m, 2H), 4.71-4.48 (m, 2H), 3.81 (s, 3H), 3.76 (m, 1H), 2.98 (m, 1H), 2.86 (m, 1H), 2.08 (m, 1H), 1.78 (m, 1H), 1.74-1.55 (m, 8H), mixture of tautomers.

Example 15 Preparation of pyridine-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(pyridine-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 19

Oxalyl chloride (4 eq., 0.213 mL, 2.52 mmol) was slowly added to the solution of picolinic acid (4 eq., 0.31 g, 2.52 mmol), N,N-diisopropylethylamine (16 eq., 1.7 6 mL, 10.1 mmol) and 4-(N,N-dimethylamino)pyridine (4 eq., 0.31 g, 2.52 mmol) in dry dichloromethane (10 mL), maintained under magnetic stirring at 0° C. After 5 minutes 3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester hydrochloride (0.42 g, 0.63 mmol) was added at 0° C. The mixture was allowed to warm to room temperature and stirring was continued for 4 hours. After evaporation of the solvent, the mixture was diluted with dichloromethane (100 mL), washed with saturated sodium hydrogenocarbonate, dried over sodium sulfate, evaporated to dryness and treated with triethylamine (5 mL) and methanol (20 mL) at room temperature for 20 hours. After removal of the solvent, the crude material was purified by flash chromatography on silica gel, using dichloromethane-methanol-30% NH₄OH 100:10:1 as eluant. The solid thus obtained was washed with methanol (5 mL) and then diethyl ether, filtered and dried to yield the title compound as white solid (0.120 g, 29% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 13.19, 13.06 (s, 1H), 12.51, 12.18 (s, 1H), 10.83, 10.79 (s, 1H), 8.65 (m, 1H), 8.43 (m, 1H), 8.17, 8.15 (m, 1H), 8.07 (ddd, J1=8.41 Hz, J2=7.68 Hz, J3=1.70 Hz, 1H), 7.85, 7.76 (m, 1H), 7.69-7.61 (m, 2H), 7.57 (m, 2H), 6.82, 6.73 (m, 1H), 4.70, 4.56 (s, 2H), 3.35-3.29 (m, 4H), 2.46 (m, 4H), 2.23 (s, 3H), 1.69, 1.64 (s, 6H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

N-[2-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-isonicotinamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(pyridine-4-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 21

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 13.0-12.2 (4bs, 2H), 10.97 (bs, 1H), 8.84 (m, 2H), 8.30 (d, J=2.7 Hz, 1H), 7.99 (bs, 1H), 7.88 (m, 2H), 7.70-7.55 (m, 3H), 6.90-6.75 (2bs, 1H), 4.75-4.50 (2bs, 2H), 3.86 (m, 4H), 2.48 (m, 4H), 2.26 (s, 3H), 1.68 (s, 6H), mixture of tautomers.

Example 16 Preparation of N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-methoxy-2-(tetrahydro-pyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=tetrahydro-pyran-4-ylamino, R2=methoxy], cpd. 81

To a mixture of 2-amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-methoxy-benzamide (400 mg, 1.05 mmol), tetramethylammonium triacetoxyborohydride (413 mg, 1.57 mmol, 1.5 eq), trifluoroacetic acid (1.5 mL) and dichloromethane (10 mL), tetrahydro-pyran-4-one (0.116 mL, 1.26 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 30 min., then diluted with dichloromethane (100 mL), washed with saturated sodium hydrogenocarbonate (100 mL), dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography, using dichloromethane-ethyl acetate 1/1 as eluant, affording the title compound as white solid (358 mg).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.44, 12.15 (2s, 1H), 10.47 (bs, 1H), 8.11 (m, 1H), 7.80-7.57 (m, 4H), 6.31-6.14 (m, 2H), 4.57, 4.50 (2s, 2H), 3.85 (m, 2H), 3.81, 3.79 (2s, 3H), 3.67 (m, 1H), 3.51 (m, 2H), 1.97 (m, 2H), 1.68, 1.63 (2s, 6H), 1.41 (m, 2H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 95

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.39, 12.08 (s, 1H), 10.31 (s, 1H), 8.15 (m, bs, 1H), 7.70-7.58 (m, bs, 4H), 6.24 (m, bs, 1H), 6.12 (bs, 1H), 4.56, 4.51 (bs, 2H), 3.85 (m, 2H), 3.70 (m, bs, 1H), 3.52 (m, 2H), 3.27 (m, 4H), 2.45 (m, 4H), 2.24 (s, 3H), 1.96 (m, bs, 2H), 1.66, 1.64 (bs, 6H), 1.39 (m, bs, 2H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-morpholin-4-yl-2-(tetrahydro-pyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=tetrahydro-pyran-4-ylamino, R2=morpholin-4-yl], cpd. 80

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.40, 12.10 (s, 1H), 10.33 (s, 1H), 8.15 (m, bs, 1H), 7.73-7.60 (m, bs, 4H), 6.28, 6.18 (m, bs, 1H), 6.14 (m, bs, 1H), 4.56, 4.50 (m, bs, 2H), 3.85 (m, 2H), 3.74 (m, 5H), 3.52 (m, 2H), 3.23 (m, 4H), 1.96 (m, bs, 2H), 1.67, 1.63 (bs, 6H), 1.41 (m, bs, 2H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=tetrahydro-pyran-4-ylamino], cpd. 78

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.50, 12.23 (s, 1H), 10.71, 10.68 (s, 1H), 7.77-7.58 (m, 5H), 7.84 (m, 1H), 6.86 (m, 1H), 6.62 (m, 1H), 4.59, 4.51 (s, 2H), 3.87 (m, 2H), 3.65 (bs, 1H), 3.50 (m, 2H), 1.96 (m, 2H), 1.69, 1.64 (s, 6H), 1.42 (m, 2H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-dimethylamino-2-(tetrahydro-pyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=tetrahydro-pyran-4-ylamino, R2=dimethylamino], cpd. 79

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.36, 12.05 (2bs, 1H), 10.22 (bs, 1H), 8.22 (m, 1H), 7.65 (m, 1H), 7.60 (m, 2H), 6.1-6.0 (m, 1H), 5.87 8m, 1H), 4.60-4.45 (m, 2H), 3.90-3.80 (m, 2H), 3.68 (m, 1H), 3.52 (m, 2H), 2.98 (bs, 6H), 1.99 (m, 2H), 1.70-1.60 (m, 6H), 1.50-1.35 (m, 2H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-(tetrahydro-pyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl, R1=tetrahydro-pyran-4-ylamino, R2=fluoro], cpd. 124

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.51, 12.32 (2bs, 1H), 10.89, 10.76 (2bs, 1H), 7.71-7.57 (m, 3H), 7.26 (m, 1H), 6.70-6.61 (m, 1H), 6.52-6.32 (m, 1H), 6.12 (m, 1H), 4.63, 4.52 (2s, 2H), 3.85 (m, 2H), 3.61 (m, 1H), 3.46 (m, 2H), 1.91 (m, 2H), 1.69, 1.65 (2s, 6H), 1.42 (m, 2H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-isobutylamino-4-(4-methyl-piperazin-1-yl)-benzamide hydrochloride [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=isobutylamino, R2=4-methyl-piperazin-1-yl], cpd. 90

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.42 (s, 1H), 10.37 (bs, 1H), 7.72 (d, J1=9.03 Hz, 1H), 7.66 (m, 1H), 7.57 (m, 2H), 6.27 (dd, J1=9.03 Hz, J2=2.20 Hz, 1H), 6.10 (d, J2=2.20 Hz, 1H), 4.52 (s, 2H), 4.02 (m, bs, 2H), 3.12 (m, bs, 6H), 3.00 (d, J=6.71 Hz, 2H), 2.85, 2.84 (d, J=4.5 Hz, 3H), 1.91 (m, 1H), 1.66 (s, 6H), 1.00 (d, J=6.70 Hz, 6H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(furan-2-ylmethyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzamide hydrochloride [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, 121=(furan-2-ylmethyl)-amino, R2=4-methyl-piperazin-1-yl], cpd. 93

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.43 (s, 1H), 10.26 (bs, 1H), 8.36 (bs, 1H), 7.70 (d, J1=9.02 Hz, 1H), 7.63 (m, 1H), 7.58 (m, 2H), 7.57 (m, 1H), 6.41 (dd, J1=3.17 Hz, J2=1.83 Hz, 1H), 6.36 (dd, bs, J1=3.17 Hz, 1H), 6.29 (dd, bs, J1=9.02 Hz, J2=2.20 Hz, 1H), 6.24 (d, J2=2.20 Hz, 1H), 4.52 (s, 2H), 4.43 (s, 2H), 4.00 (m, 2H), 3.48 (m, 2H), 3.10 (m, 4H), 2.81 (d, J=4.4 Hz, 3H), 1.62 (s, 6H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(1H-imidazol-2-ylmethyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(1H-imidazol-2-ylmethyl)-amino, R2=4-methyl-piperazin-1-yl], cpd. 94

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.40, 12.04 (bs, 1H), 11.93 (bs, 1H), 10.38, 10.32 (bs, 1H), 8.39 (t, J=5.37 Hz, 1H), 7.70-7.56 (m, 4H), 7.04 (bs, 1H), 6.84 (bs, 1H), 6.31-6.14 (m, bs, 2H), 4.55 (bs, 2H), 4.38 (d, J=J=5.37 Hz, 2H), 3.24 (m, 4H), 2.41 (m, 4H), 2.22 (s, 3H), 1.65 (bs, 6H), mixture of tautomers.

2-Benzylamino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=benzylamino, R2=4-methyl-piperazin-1-yl], cpd. 96

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.40, 12.05 (bs, 1H), 10.34 (bs, 1H), 8.49 (bs, 1H), 7.73-7.56 (m, 4H), 7.40-7.34 (m, 4H), 7.27 (m, 1H), 6.23 (m, bs, 1H), 6.04 (m, bs, 1H), 4.54 (m, bs, 2H), 4.44, 4.42 (s, 2H), 3.19 (m, bs, 4H), 2.88 (m, 4H), 2.20 (s, 3H), 1.65 (bs, 6H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(4-hydroxy-benzylamino)-4-(4-methyl-piperazin-1-yl)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=4-hydroxy-benzylamino, R2=4-methyl-piperazin-1-yl], cpd. 99

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.39, 12.05 (bs, 1H), 10.33, 10.28 (s, 1H), 9.35, 9.30 (m, bs, 1H), 8.36 (m, 1H), 7.72-7.57 (m, 3H), 7.18 (d, J=8.17 Hz, 2H), 6.75 (d, J=8.17 Hz, 2H), 6.69-6.03 (m, bs, 2H), 4.55, 4.50 (bs, 2H), 4.28 (d, J=5.37 Hz, 2H), 3.21 (m, 4H), 2.40 (m, 4H), 2.22 (s, 3H), 1.67, 1.62 (s, 6H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-hydroxy-benzylamino)-4-(4-methyl-piperazin-1-yl)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=2-hydroxy-benzylamino, R2=4-methyl-piperazin-1-yl], cpd. 101

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.40, 12.03 (bs, 1H), 10.29, 9.99 (s, 1H), 9.59 (s, 1H), 8.40 (m, bs, 1H), 7.69-7.57 (m, 3H), 7.22 (d, bs, J=7.07 Hz, 1H), 7.09 (m, 1H), 6.85 (d, bs, J=7.93 Hz, 1H), 6.81-6.75 (m, 1H), 6.36-6.10 (m, bs, 2H), 4.58-4.50 (bs, 2H), 4.32 (d, J=5.61 Hz, 2H), 3.23 (m, bs, 4H), 2.41 (m, bs, 4H), 2.23, 2.20 (s, 3H), 1.65 (bs, 6H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-thiopyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=tetrahydro-thiopyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 97

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.35, 12.03 (s, 1H), 10.26 (s, 1H), 8.17 (m, 1H), 7.66-7.50 (m, 4H), 6.26-6.09 (m, 1H), 6.04 (m, 1H), 4.54-4.42 (m, 2H), 3.57 (m, 1H), 3.21 (m, 4H), 2.72-2.62 (m (m, 4H), 2.38 (m, 4H), 2.18 (s, 3H), 2.12 (m, 2H), 1.66-1.48 (m, 8H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[((R)-1-methyl-pyrrolidin-2-ylmethyl)-amino]-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=((R)-1-methyl-pyrrolidin-2-ylmethyl)-amino, R2=4-methyl-piperazin-1-yl], cpd. 100

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.89 (d, J=8.80 Hz, 1H), 7.69-7.57 (m, 3H), 6.88 (m, bs, 1H), 6.83 (d, bs, J=8.80 Hz, 1H), 4.64 (s, 2H), 4.56, 3.13-2.73 (m, bs, 9H), 2.67 (s, 3H), 2.45 (m, 4H), 2.24 (s, 3H), 1.86-1.28 (m, bs, 10H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[((R)-1-methyl-pyrrolidin-2-ylmethyl)-amino]-4-morpholin-4-yl-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=((R)-1-methyl-pyrrolidin-2-ylmethyl)-amino, R2=morpholin-4-yl], cpd. 87

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.90 (d, J=8.90 Hz, 1H), 7.69-7.58 (m, 3H), 6.90 (m, bs, 1H), 6.85 (d, bs, J=8.90 Hz, 1H), 4.64 (s, 2H), 3.75 (m, 4H), 3.20-2.87 (m, bs, 7H), 2.78 (m, bs, 2H), 2.68 (s, 3H), 1.83 (m, bs, 1H), 1.70-1.56 (m, bs, 8H), 1.31 (m, bs, 1H).

N-[5-(2-Fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=2-fluorophenyl, R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 109

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.38, 12.06 (2s, 1H), 10.35, 10.30 (2s, 1H), 8.15 (m, 1H), 7.91 (m, 1H), 7.78-7.54 (m, 2H), 7.52-7.38 (m, 2H), 6.33-6.07 (m, 2H), 4.64-4.59 (2s, 2H), 3.84 (m, 2H), 3.70 (m, 1H), 3.52 (m, 2H), 3.27 (m, 4H), 2.45 (m, 4H), 2.24 (s, 3H), 1.96m (m, 2H), 1.61, 1.55 (2s, 6H), 1.40 (m, 2H), mixture of tautomers.

N-[5-(3,5-Dichloro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-dichlorophenyl, R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 110

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.35 (bs, 1H), 10.41 (bs, 1H), 8.21 (m, 1H), 8.01 (m, 1H), 7.86 (m, 2H), 7.73-7.66 (m, 1H), 6.28 (m, 1H), 6.20 (m, 1H), 4.52 (bs, 2H), 4.08-3.99 (m, 2H), 3.89-3.82 (m, 2H), 3.73 (m, 1H), 3.52 (m, 4H), 3.2-3.0 (m, 4H), 2.88 (bs, 3H), 1.97 (m, 2H), 1.66 (s, 6H), 1.41 (m, 2H).

N-[5-(3-Chloro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3-chlorophenyl, R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 111

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.39, 12.06 (2bs, 1H), 10.30 (bs, 1H), 8.15 (m, 1H), 7.90-7.85 (m, 2H), 7.78 (m, 1H), 7.66 (m, 2H), 6.31-6.15 (m, 1H), 6.12 (m, 1H), 4.51, 4.45 (2bs, 2H), 3.84 (m, 2H), 3.69 (m, 1H), 3.52 (m, 2H), 3.27 (m, 4H), 2.45 (m, 4H), 2.25 (bs, 3H), 1.96 (m, 2H), 1.67, 1.63 (2bs, 6H), 1.40 (m, 2H), mixture of tautomers.

N-[5-(2,6-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=2,6-difluorophenyl, R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 113

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.39, 12.06 (2bs, 1H), 10.37, 10.32 (2bs, 1H), 8.15 (m, 1H), 7.78-7.55 (m, 1H), 7.32 (m, 1H), 7.66 (m, 2H), 6.31-6.15 (m, 1H), 6.13 (m, 1H), 4.69, 4.64 (2bs, 2H), 3.84 (m, 2H), 3.71 (m, 1H), 3.52 (m, 2H), 3.28 (m, 4H), 2.45 (m, 4H), 2.24 (s, 3H), 1.96 (m, 2H), 1.62, 1.59 (2bs, 6H), 1.39 (m, 2H), mixture of tautomers.

N-[6,6-Dimethyl-5-(thiophene-2-sulfonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=thiophen-2-yl, R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 112

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.39, 12.06 (2bs, 1H), 10.32 (bs, 1H), 8.13 (m, 1H), 7.97 (m, 1H), 7.75-7.54 (m, 2H), 7.21 (m, 1H), 6.32-6.09 (m, 2H), 4.51 (m, 2H), 3.84 (m, 2H), 3.70 (m, 1H), 3.52 (m, 2H), 3.32 (m, 4H), 2.45 (m, 4H), 2.24 (s, 3H), 1.96 (m, 2H), 1.66 (bs, 6H), 1.40 (m, 2H), mixture of tautomers.

N-[5-(3-Methoxy-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3-methoxyphenyl, R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 115

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.36, 12.04 (2bs, 1H), 10.20 (bs, 1H), 8.14 (m, 1H), 7.70-7.43 (m, 3H), 7.33 (m, 1H), 7.25 (m, 1H), 6.31-6.15 (m, 1H), 6.12 (m, 1H), 4.48, 4.41 (2bs, 2H), 3.88-3.80 (m, 5H), 3.70 (m, 1H), 3.52 (m, 2H), 3.27 (m, 4H), 2.44 (m, 4H), 2.24 (s, 3H), 1.96 (m, 2H), 1.69, 1.63 (2bs, 6H), 1.39 (m, 2H), mixture of tautomers.

N-[6,6-Dimethyl-5-(pyridine-3-sulfonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=pyridin-3-yl, R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 114

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.39, 12.06 (2bs, 1H), 10.30 (bs, 1H), 9.05 (m, 1H), 8.85 (m, 1H), 8.31 (m, 1H), 8.11 (m, 1H), 7.71-7.52 (m, 2H), 6.32-6.15 (m, 1H), 6.12 (m, 1H), 4.54, 4.48 (2bs, 2H), 3.85 (m, 2H), 3.69 (m, 1H), 3.52 (m, 2H), 3.27 (m, 4H), 2.44 (m, 4H), 2.24 (s, 3H), 1.96 (m, 2H), 1.66, 1.63 (2bs, 6H), 1.40 (m, 2H), mixture of tautomers.

N-[5-(3-Fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3-fluorophenyl, R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 104

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.43, 12.08 (2bs, 1H), 10.39, 10.34 (2bs, 1H), 8.15 (m, 1H), 7.74 (m, 1H), 7.72-7.63 (m, 3H), 7.54 (m, 1H), 6.25 (m, 1H), 6.18 (m, 1H), 4.48 (bs, 2H), 3.84 (m, 2H), 3.71 (m, 1H), 3.51 (m, 2H), 3.50-3.35 (m, 8H), 2.83 (s, 3H), 1.94 (m, 2H), 1.63 (bs, 6H), 1.39 (m, 2H), mixture of tautomers.

Example 17 Preparation of N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(piperidin-3-ylmethyl)-amino]-benzamide [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=(piperidin-3-ylmethyl)-amino], cpd. 88

To a solution of 2-amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide (100 mg, 0.223 mmol) in N,N-dimethylformamide (2.5 mL) were added sodium triacetoxyborohydride (240 mg, 1.12 mmol, 5 eq), 3-formyl-piperidine-1-carboxylic acid tert-butyl ester (145 mg, 0.67 mmol, 3 eq) and trifluoroacetic acid (0.25 mL). The reaction mixture was stirred at room temperature overnight, then 4N hydrochloric acid in 1,4-dioxane (5 mL) and dichloromethane (5 mL) were added, the mixture stirred for additional 5 hours, concentrated under vacuum, basified with 2N NaOH, extracted with dichloromethane and dried over sodium sulfate. After evaporation of the solvent, the crude was purified by flash chromatography on silica gel using dichloromethane-methanol-30% NH₄OH 100:10:1 as eluant, affording the title compound as white solid (42 mg).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.43 (bs, 1H), 12.72 (bs, 1H), 7.76-7.71 (m, 2H), 7.66 (m, 1H), 7.60 (m, 2H), 7.35 (m, 1H), 6.78 (d, bs, J=8.90 Hz, 1H), 6.61 (m, 1H), 4.58 (bs, 2H), 3.22-3.05 (m, 6H), 2.66 (m, 1H), 1.92-1.19 (m, bs, 10H).

Operating in an analogous way, the following compounds were obtained:

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[((S)-1-pyrrolidin-2-ylmethyl)-amino]-benzamide hydrochloride [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=((S)-1-pyrrolidin-2-ylmethyl)-amino], cpd. 76

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.80 (s, 1H), 9.12 (bs, 1H), 8.67 (bs, 1H), 7.74 (dd, J1=7.92 Hz, J2=1.47 Hz, 1H), 7.67 (m, 1H), 7.61 (m, 2H), 7.38 (ddd, J1=8.90 Hz, J2=7.08 Hz, J2=1.47 Hz, 1H), 6.88 (d, J=8.90 Hz, 1H), 6.69 (dd, bs, J1=7.92 Hz, J2=7.08 Hz, 1H), 4.61 (s, 2H), 3.74 (m, 1H), 3.52 (m, 2H), 3.21 (m, 2H), 2.13 (m, 1H), 2.03-1.83 (m, 2H), 1.67 (m, 7H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-morpholin-4-yl-2-[(((R)-1-pyrrolidin-2-ylmethyl)-amino]-benzamide hydrochloride [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=((R)-1-pyrrolidin-2-ylmethyl)-amino, R2=morpholin-4-yl], cpd. 77

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.46 (s, 1H), 9.19 (bs, 1H), 8.69 (bs, 1H), 7.71 (d, J1=9.02 Hz, 1H), 7.66 (m, 1H), 7.60 (m, 2H), 6.30 (dd, J1=9.02 Hz, J2=1.95 Hz, 1H), 6.15 (d, J2=1.95 Hz, 1H), 4.58 (s, 2H), 3.75 (m, 4H), 3.58-3.30 (m, 5H), 3.27 (m, 4H), 2.12 (m, 1H), 2.02-1.84 (m, 2H), 1.72-1.66 (m, 7H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[((R)-1-pyrrolidin-2-ylmethyl)-amino]-benzamide dihydrochloride [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=((R)-pyrrolidin-2-ylmethyl)-amino, R2=4-methyl-piperazin-1-yl], cpd. 91

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.75 (bs, 1H), 10.52 (bs, 1H), 8.27 (bs, NH₂ ⁺), 7.73 (d, J1=9.03 Hz, 1H), 7.66 (m, 1H), 7.60 (m, 2H), 6.34 (dd, J1=9.03 Hz, J2=2.31 Hz, 1H), 6.23 (d, J2=2.31 Hz, 1H), 4.59 (s, 2H), 4.09 (m, 2H), 3.77-3.08 (m, 11H), 2.84 (d, 3H), 2.17-1.61 (m, 4H), 1.65 (s, 6H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[((S)-1-pyrrolidin-2-ylmethyl)-amino]-benzamide dihydrochloride [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=((S)-1-pyrrolidin-2-ylmethyl)-amino, R2=4-methyl-piperazin-1-yl], cpd. 92

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.75 (bs, 1H), 10.52 (bs, 1H), 8.27 (bs, NH2+), 7.73 (d, J1=9.03 Hz, 1H), 7.66 (m, 1H), 7.60 (m, 2H), 6.34 (dd, J1=9.03 Hz, J2=2.31 Hz, 1H), 6.23 (d, J2=2.31 Hz, 1H), 4.59 (s, 2H), 4.09 (m, 2H), 3.77-3.08 (m, 11H), 2.84 (d, 3H), 2.17-1.61 (m, 4H), 1.65 (s, 6H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(piperidin-4-ylamino)-benzamide dihydrochloride [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=piperidin-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 98

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.79 (bs, 1H), 10.47 (s, 1H), 9.16 (bs, 1H), 8.88 (bs, 1H), 8.55 (bs, 1H), 8.15 (bs, 1H), 7.70 (d, J1=9.07 Hz, 1H), 7.63 (m, 1H), 7.58 (m, 2H), 6.29 (dd, bs, J1=9.07 Hz, J2=1.93 Hz, 1H), 6.17 (d, bs, J2=1.93 Hz, 1H), 4.54 (s, 2H), 4.01 (m, 2H), 3.78 (m, 1H), 3.49-3.01 (m, 10H), 2.81 (d, 3H), 2.56 (m, 2H), 2.10 (m, 2H), 1.64-1.53 (m, 8H)

Example 18 Preparation of N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3-ethyl-ureido)-4-(4-methyl-piperazin-1-yl)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=3-ethyl-ureido, R2=4-methyl-piperazin-1-yl], cpd. 127

To a solution of 3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (308 mg, 0.5 mmol) in tetrahydrofuran (20 mL) ethyl isocyanate (0.119 mL, 1.5 mmol, 3 eq) was added and the mixture stiffed at 50° C. for 24 hours. Additional ethyl isocyanate (1.2 mL) was then added, the mixture stirred at 50° C. for 4 days and then evaporated to dryness. The residue was treated with 10 mL of methanol/triethylamine 8:2, stirred at room temperature for 4 hours and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane-methanol-30% NH₄OH 96:4:0.4 then 90:10:1 as eluant affording the title compound as white solid (183 mg).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.48, 12.05 (2s, 1H), 10.65 (bs, 1H), 10.25, 10.16 (bs, 1H), 8.00 (m, 1H), 7.75-7.60 (m, 4H), 7.22 (bs, 1H), 6.66-6.47 (m, 1H), 4.65, 4.57 (2bs, 2H), 3.26 (m, 4H), 3.10 (m, 2H), 2.46 (m, 4H), 2.24 (s, 3H), 1.68, 1.64 (2s, 6H), 1.08 (t, 3H), mixture of tautomers.

Example 19 Preparation of morpholine-4-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(morpholine-4-carbonyl)-amino, R2=4-methyl-piperazin-1-yl], cpd. 130

A mixture of 3-[2-Amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (308 mg, 0.5 mmol), N,N-diisopropylethylamine (0.104 mL, 0.6 mmol, 1.2 eq), morpholine-4-carbonyl chloride (1.2 mL, 10 mmol, 20 eq) and tetrahydrofuran (20 mL) was stirred at 60° C. for 7 days. The reaction mixture was then poured into water (100 mL), extracted with dichloromethane (100 mL), dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel (acetone as eluant) affording 112 mg of 5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-{4-(4-methyl-piperazin-1-yl)-2-[(morpholine-4-carbonyl)-amino]-benzoylamino}-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester that was treated with 10 mL of methanol/triethylamine 8:2 and stirred at room temperature overnight. The mixture was evaporated to dryness and the residue purified by flash chromatography on silica gel using dichloromethane-methanol-30% NH₄OH 96:4:0.4 as eluant, yielding the title compound as white solid (50 mg).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.53, 12.23 (2s, 1H), 11.14, 11.25 (2s, 1H), 10.78, 10.75 (2s, 1H), 8.05 (m, 1H), 7.88, 7.75 (2m, 1H), 7.67 (m, 1H), 7.60 (m, 2H), 6.68, 6.59 (2m, 1H), 4.60, 4.52 (2s, 2H), 3.65 (m, 4H), 3.45 (m, 4H), 3.28 (m, 4H), 2.46 (m, 4H), 2.24 (s, 3H), 1.68, 1.65 (2s, 6H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3,3-dimethyl-ureido)-4-(4-methyl-piperazin-1-yl)-benzamide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=3,3-dimethyl-ureido, R2=4-methyl-piperazin-1-yl], cpd. 128

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.52, 12.17 (2s, 1H), 11.38, 11.17 (2s, 1H), 10.75, 10.72 (2s, 1H), 8.11 (m, 1H), 7.89, 7.74 (2m, 1H), 7.67 (m, 1H), 7.59 (m, 2H), 6.67, 6.57 (m, 1H), 4.56, 4.51 (2s, 2H), 3.28 (m, 4H), 2.99 (s, 6H), 2.46 (m, 4H), 2.24 (s, 3H), 1.69, 1.65 (2s, 6H), mixture of tautomers.

Pyrrolidine-1-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide [(I) Ra=Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=(pyrrolidine-1-carbonyl)-amino, R2=4-methyl-piperazin-1-yl], cpd. 129

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.52, 12.17 (2s, 1H), 11.17, 10.98 (2s, 1H), 10.74, 10.72 (2s, 1H), 8.13 (m, 1H), 7.87, 7.74 (2m, 1H), 7.68 (m, 1H), 7.58 (m, 2H), 6.65, 6.56 (2m, 1H), 4.58, 4.52 (2s, 2H), 3.40 (m, 4H), 3.30 (m, 4H), 2.50 (m, 4H), 2.28 (bs, 3H), 1.93 (m, 4H), 1.69, 1.65 (2s, 6H), mixture of tautomers.

Example 20 Preparation of N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-3-(tetrahydro-pyran-4-ylamino)-isonicotinamide [(I) Ra=Rb=methyl, A=D=E=CH, B=N, R=3,5-difluorophenyl, R1=tetrahydro-pyran-4-ylamino], cpd. 117

Step 1 Preparation of 3-(tetrahydro-pyran-4-ylamino)-isonicotinic acid methyl ester

To a mixture of 3-amino-isonicotinic acid methyl ester (500 mg, 3.29 mmol), dry N,N-dimethylformamide (10 mL), trifluoroacetic acid (1 mL) and sodium triacetoxyborohydride (1.4 g, 6.6 mmol, 2 eq) was added tetrahydro-pyran-4-one (0.5 mL, 4.94 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 24 hours then poured into saturated sodium hydrogenocarbonate (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and evaporated to dryness affording the crude title compound as yellow syrup that was used as such for the next step.

Step 2 Preparation of 3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-isonicotinic acid

The crude 3-(tetrahydro-pyran-4-ylamino)-isonicotinic acid methyl ester (3.29 mmol) was treated with 0.5 N sodium hydroxide (6.6 mL, 3.3 mmol) and methanol (15 mL) and stirred at 75° C. for 2 hours. An additional amount of 0.5 N sodium hydroxide (0.4 mL) was then added and the stirring continued for 2 hours at 75° C. Hydrochloric acid (0.5 N) was then added until acidic pH and the mixture evaporated to dryness. The residue was then suspended in trifluoroacetic anhydride (5 mL) and dichloromethane (5 mL), stirred at room temperature for 1 h, evaporated to dryness, treated with water (10 mL) and stirred at room temperature for 30 minutes. The precipitated material was filtered, washed with water then with diethyl ether and dried affording the title compound as white solid (829 mg).

1H-NMR (400 MHz), 6: (ppm, DMSO-d₆): 8.88 (d, J=5.0 Hz, 1H), 8.77 (s, 1H), 7.94 (d, J=5.0 Hz, 1H), 4.57 (m, 1H), 3.84 (m, 2H), 3.41 (m, 2H), 1.95 (m, 1H), 1.60 (m, 1H), 1.47 (m, 1H), 1.08 (m, 1H).

Step 3 Preparation of 3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-isonicotinoyl chloride

To a suspension of 3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-isonicotinic acid (350 mg, 1.1 mmol) in dry dichloromethane (15 mL) and oxalyl chloride (0.65 mL, 6.6 mmol, 6 eq) a drop of N,N-dimethylformamide was added. The mixture was stirred at room temperature for 1 h and then evaporated to dryness affording the crude title compound that was used as such for the next step.

Step 4 Preparation of 3-({3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-pyridine-4-carbonyl}-amino)-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester [(IV) Q=Ethyl, Ra=Rb=methyl, A=D=E=CH, B=N, R1=(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]

To a mixture of 3-amino-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (244 mg, 0.75 mmol), dry tetrahydrofuran (30 mL) and N,N-diisopropylethylamine (0.75 mL, 4.4 mmol) was added 3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]isonicotinoyl chloride (1.1 mmol). The mixture was stirred at 45° C. for 1 h, then evaporated to dryness, diluted with dichloromethane (100 mL), washed with saturated sodium hydrogenocarbonate (100 mL), dried over sodium sulfate and evaporated to dryness affording the crude title compound that was used as such for the next step.

Step 5 Preparation of 3-({3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-pyridine-4-carbonyl}-amino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carb oxylic acid ethyl ester hydrochloride [(V) Q=Ethyl, Ra=Rb=methyl, A=D=E=CH, B=N, R1=(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]

A mixture of 3-({3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-pyridine-4-carbonyl}-amino)-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (0.75 mmol), dichloromethane (20 mL) and 4N hydrochloric acid in 1,4-dioxane (3 mL) was stiffed at room temperature overnight and then evaporated to dryness. The residue was stirred with diethyl ether, filtered, and dried affording the crude title compound that was used as such for the next step.

Step 6 Preparation of N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-3-(tetrahydro-pyran-4-ylamino)-isonicotinamide [(I) Ra=Rb=methyl, A=D=E=CH, B=N, R=3,5-difluorophenyl, R1=tetrahydro-pyran-4-ylamino], cpd. 117

To a mixture of 3-({3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-pyridine-4-carbonyl}-amino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester hydrochloride (0.75 mmol), dry dichloromethane (50 mL) and triethylamine (0.84 mL, 6 mmol) was added 3,5-difluorobenzenesulfonyl chloride (478 mg, 2.25 mmol). The mixture was stirred at room temperature for 4 hours then methanol (10 mL) and triethylamine (5 mL) were added. The mixture was then heated to 60° C. and the stiffing continued for 2 hours. The solvents were evaporated and the crude residue purified by flash chromatography on silica gel, affording the title compound as pale yellow solid (100 mg).

1H-NMR (400 MHz),

(ppm, DMSO-d₆): 12.59, 12.35 (2s, 1H), 11.04, 11.02 (2s, 1H), 8.87, 8.82 (2s, 1H), 7.93, 7.86 (2m, 1H), 7.71-7.52 (m, 4H), 7.28 (d, 1H), 4.61, 4.52 (2s, 2H), 3.86 (m, 2H), 3.81 (m, 1H), 3.50 (m, 2H), 1.98 (m, 2H), 1.68, 1.64 (2s, 6H), 1.44 (m, 2H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

3-(Tetrahydro-pyran-4-ylamino)-pyridine-2-carboxylic acid [5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-amide [(I) Ra=Rb=methyl, A=B=D=CH, E=N, R=3,5-difluorophenyl, R1=tetrahydro-pyran-4-ylamino], cpd. 121

1H-NMR (400 MHz), 6. (ppm, DMSO-d₆): 12.57, 12.14 (2s, 1H), 11.11, 10.35 (2s, 1H), 8.19 (d, J=7.8 Hz, 1H), 7.90 (m, 1H), 7.69-7.59 (m, 3H), 7.47-7.40 (m, 2H), 4.70, 4.65 (2s, 2H), 3.89 (m, 2H), 3.73 (m, 1H), 3.50 (m, 2H), 1.97 (m, 2H), 1.67, 1.62 (2s, 6H), 1.47 (m, 2H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(4-hydroxy-cyclohexylamino)-nicotinamide [(I) Ra=Rb=methyl, A=N, B=D=E=CH, R=3,5-difluorophenyl, R1=4-hydroxy-cyclohexylamino], cpd. 118

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.53, (bs, 1H), 10.84 (bs, 1H), 8.21 (m, 1H), 8.12-7.98 (m, 2H), 7.70-7.59 (m, 3H), 6.58 (m, 1H), 4.57 (m, 3H), 3.90 (m, 1H), 3.49 (m, 1H), 2.00 (m, 2H), 1.84 (m, 2H), 1.64 (s, 6H), 1.28 (m, 4H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(tetrahydro-furan-2-ylmethyl)-amino]-nicotinamide [(I) Ra=Rb=methyl, A=N, B=D=E=CH, R=3,5-difluorophenyl, R1=(tetrahydro-furan-2-ylmethyl)-amino], cpd. 149

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.54, 12.22 (2bs, 1H), 10.86 (bs, 1H), 8.31-7.97 (m, 3H), 7.64 (m, 1H), 7.59 (m, 2H), 6.58 (m, 1H), 4.61-4.44 (m, 2H), 4.02 (m, 1H), 3.81 (m, 1H), 3.67 (m, 1H), 3.58 (m, 1H), 3.43 (m, 1H), 2.00-1.77 (m, 3H), 1.67 (bs, 6H), 1.56 (m, 1H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3-hydroxy-propylamino)-nicotinamide [(I) Ra=Rb=methyl, A=N, B=D=E=CH, R=3,5-difluorophenyl, R1=3-hydroxy-propylamino], cpd. 150

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.53, 12.25 (2bs, 1H), 10.84 (bs, 1H), 8.27-7.98 (m, 3H), 7.69-7.58 (m, 3H), 6.67-6.52 (m, 1H), 4.66-4.46 (m, 3H), 3.50 (m, 4H), 1.75-1.60 (m, 8H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(4-methoxy-benzylamino)-nicotinamide [(I) Ra=Rb=methyl, A=N, B=D=E=CH, R=3,5-difluorophenyl, R1=4-methoxy-benzylamino], cpd. 151

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.52, 12.25 (2bs, 1H), 10.87 (bs, 1H), 8.42-8.00 (m, 3H), 7.67-7.55 (m, 3H), 7.26 (m, 2H), 6.87 (m, 2H), 6.74-6.52 (m, 1H), 4.63-4.46 (m, 4H), 3.72 (s, 3H), 1.65 (bs, 6H), mixture of tautomers.

Example 21 Preparation of N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(isopropylamino-methyl)-benzamide hydrochloride [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=isopropylamino-methyl], cpd. 139

Step 1 Preparation of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoic acid

To a solution of 3H-isobenzofuran-1-one (18 g, 134 mmol) in dry N,N-dimethylformamide (110 mL) was added potassium phthalimide (27 g, 145 mmol). The mixture was stirred at reflux for 6 hours then cooled to 0° C. and treated with 1N hydrochloric acid (180 mL). The yellow solid thus formed was filtered, washed with water, with ethanol and dried in oven. Crystallization with ethanol afforded the title compound as white solid (27 g).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 13.21 (bs, 1H), 7.97-7.86 (m, 5H), 7.50 (m, 1H), 7.40 (m, 1H), 7.17 (m, 1H), 5.17 (s, 2H).

Step 2 Preparation of 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester

To a suspension of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoic acid (1.35 g, 4.8 mmol) in dry dichloromethane (30 mL), at 0° C., under stirring, was added oxalyl chloride (2.1 mL, 24 mmol) and dry N,N-dimethylformamide (35 microL). The mixture was allowed to warm to room temperature, stirred for 1.5 hours then evaporated to dryness. The residue was diluted with dry toluene and evaporated again. The crude acyl chloride thus obtained (yellow solid) was dissolved in dry tetrahydrofuran (20 mL) and treated with N,N-diisopropylethylamine (2.5 mL, 15 mmol) and with a solution of 3-amino-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (1.3 g, 4 mmol) in 15 mL of dry tetrahydrofuran. The mixture was stirred at room temperature for 2 days then evaporated to dryness. The residue was dissolved in dichloromethane, washed with 1N HCl, water, saturated solution of NaHCO₃, brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol 98.5:1.5 as the eluant affording the title compound as white solid (1.5 g).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.63 (bs, 1H), 7.91-7.83 (m, 4H), 7.71 (m, 1H), 7.58-7.46 (m, 2H), 7.37 (m, 1H), 5.07 (s, 2H), 4.53 (bs, 2H), 4.43 (m, 2H), 1.63 (bs, 6H), 1.50 (s, 9H), 1.37 (m, 3H).

Step 3 Preparation of 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester hydrochloride

To a suspension of 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (1.5 g, 2.5 mmol) in 1,4-dioxane (20 mL) was added 4N HCl in 1,4-dioxane (14 mL, 56 mmol). After stirring at room temperature overnight the volatiles were removed under reduced pressure and the residue triturated with diethylether affording the title compound as white solid (1.24 g).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.75 (bs, 1H), 9.89 (bs, 2H), 7.91-7.83 (m, 4H), 7.72 (m, 1H), 7.58-7.46 (m, 2H), 7.37 (m, 1H), 5.07 (s, 2H), 4.61 (bs, 2H), 4.45 (q, J=7.1 Hz, 2H), 1.69 (s, 6H), 1.36 (t, J=7.1 Hz, 3H).

Step 4 Preparation of 5-(3,5-difluoro-benzenesulfonyl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester

To a suspension of 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester hydrochloride (1.24 g, 2.4 mmol) in dry dichloromethane (30 mL) was added N,N-diisopropylethylamine (1.67 mL, 9.6 mmol) and 3,5-difluorobenzenesulfonyl chloride (0.77 g, 3.6 mmol). After stirring at room temperature for 3 hours the mixture was diluted with dichloromethane (50 mL), washed with 1N HCl, water, saturated solution of NaHCO₃, brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel eluting with ethyl acetate and then with dichloromethane/methanol 98:2 affording the title compound as white solid (1.4 g).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.61 (bs, 1H), 7.83 (m, 4H), 7.69-7.63 (m, 4H), 7.56-7.45 (m, 2H), 7.39 (m, 1H), 5.05 (s, 2H), 4.72 (bs, 2H), 4.41 (q, J=7.1 Hz, 2H), 1.67 (s, 6H), 1.34 (t, J=7.1 Hz, 3H).

Step 5 Preparation of 2-aminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide

To a suspension of 5-(3,5-difluoro-benzenesulfonyl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (0.23 g, 0.34 mmol) in methanol (15 mL) and dichloromethane (1.5 mL) was added hydrazine hydrate (50 microL, 1.02 mmol). After stirring at reflux for 1 hour the volatiles were removed under reduced pressure and the residue purified by flash chromatography on silica gel eluting with dichloromethane/methanol/7N NH₃ in methanol 95:4:1 affording the title compound as colorless oil (93 mg).

ESI (+) MS: m/z 462 (MH⁺).

Step 6 Preparation of N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(isopropylamino-methyl)-benzamide hydrochloride [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=isopropylamino-methyl], cpd. 139

To a solution of 2-aminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide (93 mg, 0.2 mmol) in dichloromethane (6 mL) was added acetone (22 microL, 0.3 mmol), sodium triacetoxyborohydride (59 mg, 0.28 mmol) and acetic acid (171 microL, 3 mmol). After stirring for 3.5 hours at room temperature the mixture was treated with 1M NaOH (3 mL). The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol/7N NH₃ in methanol 95:4:1. The oil thus obtained was dissolved in dichloromethane (2 mL) and added with 2N HCl in Et₂O (0.4 mL). Evaporation of the volatiles afforded 56 mg of the title compound as white solid.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.33 (bs, 1H), 8.61 (bs, 2H), 7.82 (m, 1H), 7.72-7.51 (m, 6H), 4.61 (s, 2H), 4.23 (m, 2H), 3.43 (m, 1H), 1.69 (s, 6H), 1.33 (d, J=6.5 Hz, 6H).

Operating in an analogous way, the following compounds were obtained:

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(tetrahydro-pyran-4-ylamino)-methyl]-benzamide hydrochloride [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=[(tetrahydro-pyran-4-ylamino)-methyl], cpd. 141

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.36 (bs, 1H), 8.82 (bs, 2H), 7.83 (m, 1H), 7.73-7.52 (m, 6H), 4.68 (s, 2H), 4.30 (m, 2H), 3.97 (m, 2H), 3.50-3.30 (m, 3H), 2.06 (m, 2H), 1.73 (m, 2H), 1.69 (s, 6H).

2-Cyclobutylaminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide hydrochloride [(I) Ra=Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=cyclobutylaminomethyl], cpd. 142

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.30 (bs, 1H), 8.96 (bs, 2H), 7.82 (m, 1H), 7.75-7.53 (m, 6H), 4.65 (s, 2H), 4.14 (m, 2H), 3.37 (m, 1H), 2.35-2.16 (m, 4H), 1.85 (m, 2H), 1.70 (s, 6H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-[(tetrahydro-pyran-4-ylamino)-methyl]-benzamide hydrochloride [(I) Ra=Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl, R1=[(tetrahydro-pyran-4-ylamino)-methyl, R2=fluoro], cpd. 135

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.44 (bs, 1H), 8.96 (bs, 2H), 7.74-7.35 (m, 7H), 4.67 (s, 2H), 4.20 (m, 2H), 3.91 (m, 2H), 3.50-3.30 (m, 3H), 2.00 (m, 2H), 1.68 (s, 6H), 1.63 (m, 2H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-(isopropylamino-methyl)-benzamide hydrochloride [(I) Ra=Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl, R1=isopropylamino-methyl, R2=fluoro], cpd. 133

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.45 (bs, 1H), 8.76 (bs, 2H), 7.73-7.39 (m, 7H), 4.63 (s, 2H), 4.16 (m, 2H), 3.40 (m, 1H), 1.71 (s, 6H), 1.31 (d, J=6.6 Hz, 6H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-morpholin-4-ylmethyl-benzamide hydrochloride [(I) Ra=Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl, R1=morpholin-4-ylmethyl, R2=fluoro], cpd. 137

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.42 (bs, 1H), 10.36 (bs, 1H), 7.72-7.57 (m, 5H), 7.45 (m, 1H), 4.64 (s, 2H), 4.37 (bs, 2H), 4.02-3.72 (m, 4H), 3.4-3.1 (m, 4H), 1.69 (s, 6H). 

1. A method for treating a disease caused by and/or associated with a dysregulated protein kinase activity which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as defined

wherein: R is an optionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl or aryl; R1 is selected from halogen, nitro, NHCOR4, NHSO₂R10, NR5R6, OR7, R8R9N—C₁-C₆ alkyl, R7O—C₁-C₆ alkyl and an optionally further substituted straight or branched C₁-C₆ alkyl, wherein: R4 is selected from hydrogen, an optionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl, aryl, NR8R9, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl; R5 and R6, being the same or different, are independently selected from hydrogen, an optionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl, aryl, R8R9N—C₂-C₆ alkyl and R7O—C₂-C₆ alkyl; R7 is selected from hydrogen, an optionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl, aryl and R8R9N—C₂-C₆ alkyl; R8 and R9, being the same or different, are independently selected from hydrogen, an optionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl and aryl, or R8 and R9, taken together with the nitrogen atom to which they are bonded, form an optionally substituted heterocycloalkyl group; R10 is an optionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl or aryl; A, B, D and E represent a nitrogen atom, CH, CR2 or CR3, with a maximum of two of A, B, D and E representing a nitrogen atom, and with a maximum of two of A, B, D and E representing CR2 or CR3, wherein: R2 and R3, being the same or different, are independently selected from halogen, trifluoromethyl, nitro, OR7, NR8R9, an optionally further substituted straight or branched C₁-C₆ alkyl, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl, wherein R7, R8, and R9 are as defined above; Ra and Rb, being the same or different, are selected from hydrogen or methyl, with the provisos that: when Ra and Rb are hydrogen atoms, and each of A, B, D and E are CH, CR2 or CR3, then R1 is not OH, OCH₃, Cl, F or CH₃; and when A, D and E are CH, and B is CR2, wherein R2 is 4-methylpiperazine or morpholine, then R1 is not trifluoromethyl, F, nitro, amino, NHCOR4^(I) wherein R4^(I) is isopropyl [—CH(CH₃)₂], cyclobutyl, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH(NH₂)CH₃ or pyrrolidin-2-yl; or isomers, tautomers, carriers, metabolite, prodrugs and pharmaceutically acceptable salt thereof.
 2. The method according to claim 1 for treating a disease caused by and/or associated with a dysregulated IGF-1R or Aurora kinases activity.
 3. The method according to claim 2 for treating a disease caused by and/or associated with a dysregulated IGF-1R activity.
 4. The method according to claim 1 wherein the disease is selected from the group consisting of cancer, cell proliferative disorders, viral infections, retinopathies including diabetic and neonatal retinopathies and age related macular degeneration, atherosclerosis and conditions involving vascular smooth muscle proliferation or neointimal formation such as restenosis following angioplasty or surgery, graft vessel disease, such as can occur following vessel or organ transplantation, acromegaly and disorders secondary to acromegaly as well as other hypertrophic conditions in which IGF/IGF-1R signalling is implicated, such as benign prostatic hyperplasia, psoriasis, fibrotic lung disease, pulmonary fibrosis, pathologies related to chronic or acute oxidative stress or hyperoxia induced tissue damage, and metabolic disorders in which elevated IGF levels or IGF-1R activity are implicated, such as obesity.
 5. The method according to claim 4 wherein the cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratocanthomas, thyroid follicular cancer and Kaposi's sarcoma.
 6. The method according to claim 4 wherein the cancer is selected from the group consisting of breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer, gastric cancer, clear cell renal cell carcinoma, uveal melanoma, multiple myeloma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi' sarcoma and medulloblastoma.
 7. The method according to claim 4 wherein the cell proliferative disorder is selected from the group consisting of benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis.
 8. The method according to claim 1 which provides tumor angiogenesis and metastasis inhibition.
 9. The method according to claim 1 further comprising subjecting the mammal in need thereof to a radiation therapy or chemotherapy regimen in combination with at least one cytostatic or cytotoxic agent.
 10. The method according to claim 1 wherein the mammal in need thereof is a human.
 11. A method for inhibiting IGF1-R activity which comprises contacting the said receptor with an effective amount of a compound of the formula

wherein: R is an optionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl or aryl; R1 is selected from halogen, nitro, NHCOR4, NHSO₂R10, NR5R6, OR7, R8R9N—C₁-C₆ alkyl, R7O—C₁-C₆ alkyl and an optionally further substituted straight or branched C₁-C₆ alkyl, wherein: R4 is selected from hydrogen, an optionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl, aryl, NR8R9, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl; R5 and R6, being the same or different, are independently selected from hydrogen, an optionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl, aryl, R8R9N—C₂-C₆ alkyl and R7O—C₂-C₆ alkyl; R7 is selected from hydrogen, an optionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl, aryl and R8R9N—C₂-C₆ alkyl; R8 and R9, being the same or different, are independently selected from hydrogen, an optionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl and aryl, or R8 and R9, taken together with the nitrogen atom to which they are bonded, form an optionally substituted heterocycloalkyl group; R10 is an optionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl or aryl; A, B, D and E represent a nitrogen atom, CH, CR2 or CR3, with a maximum of two of A, B, D and E representing a nitrogen atom, and with a maximum of two of A, B, D and E representing CR2 or CR3, wherein: R2 and R3, being the same or different, are independently selected from halogen, trifluoromethyl, nitro, OR7, NR8R9, an optionally further substituted straight or branched C₁-C₆ alkyl, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl, wherein R7, R8, and R9 are as defined above; Ra and Rb, being the same or different, are selected from hydrogen or methyl, with the provisos that: when Ra and Rb are hydrogen atoms, and each of A, B, D and E are CH, CR2 or CR3, then R1 is not OH, OCH₃, Cl, F or CH₃; and when A, D and E are CH, and B is CR2, wherein R2 is 4-methylpiperazine or morpholine, then R1 is not trifluoromethyl, F, nitro, amino, NHCOR4^(I) wherein R4^(I) is isopropyl [—CH(CH₃)₂], cyclobutyl, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH(NH₂)CH₃ or pyrrolidin-2-yl; or isomers, tautomers, carriers, metabolite, prodrugs and pharmaceutically acceptable salt thereof.
 12. The method of claim 1 wherein R is selected from C₃-C₆ cycloalkyl, heterocycloalkyl and aryl; R1 is selected from halogen, NHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl, R7O—C₁-C₆ alkyl and an optionally further substituted straight or branched C₁-C₆ alkyl; A and D are CH or nitrogen, B is nitrogen, CH or CR2, and E is CH or CR3; R2 and R3 are independently selected from halogen, trifluoromethyl, OR7, NR8R9, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl.
 13. The method of claim 12 wherein R1 is selected from NHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl, R7O—C₁-C₆ alkyl and an optionally further substituted straight or branched C₁-C₆ alkyl; A is CH or nitrogen, B is nitrogen, CH or CR2, E is CH or CR3, and D is CH; R2 and R3 are independently selected from halogen, OR7, NR8R9, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl.
 14. The method of claim 1 wherein R is heterocycloalkyl or aryl; R1 is selected from NHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl and an optionally further substituted straight or branched C₁-C₆ alkyl; B is CH or CR2, E is CH or CR3, and A and D are CH; Ra and Rb are methyl.
 15. The method of claim 1 wherein R is aryl; B and E are CH, CR2 or CR3, and A and D are CH.
 16. The method of claim 1 wherein B is CR2, and A, D and E are CH; R2 is selected from OR7, NR8R9, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl.
 17. The method of claim 1 wherein the compound is selected from the group consisting of: (S)-Tetrahydro-furan-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; Tetrahydro-pyran-4-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; 1H-Pyrrole-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; 1H-Pyrrole-3-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; 1-Methyl-1H-pyrrole-2-carboxylic acid [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide; 1H-Pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide; 1H-Pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide; 1H-Pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide; 1H-Pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide; 1H-Pyrrole-3-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide; 1H-Pyrrole-3-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide; 1-Methyl-1H-pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide; Tetrahydro-pyran-4-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide; Tetrahydro-pyran-4-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide; N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-dimethylamino-2-(tetrahydro-pyran-4-ylamino)-benzamide; N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-morpholin-4-yl-2-(tetrahydro-pyran-4-ylamino)-benzamide; N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; 1H-Pyrrole-2-carboxylic acid {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-3-fluoro-phenyl}-amide; N-[5-(3-Chloro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; N-[5-(3-Fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide; N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide and N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide or pharmaceutically acceptable salt thereof. 